Qingxia Huang, Yongjie Wang, Karina Farias ...
· Cardiovascular research
· Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021.
· pubmed
Cardiomyocyte senescence is a hallmark of cardiac aging and closely associated with diastolic dysfunction and heart failure in older adults. Strategies to effectively delay or reverse cardiomyocyte senescence in the aged heart remain limited. We investigated whether NAD+ replenis...
Cardiomyocyte senescence is a hallmark of cardiac aging and closely associated with diastolic dysfunction and heart failure in older adults. Strategies to effectively delay or reverse cardiomyocyte senescence in the aged heart remain limited. We investigated whether NAD+ replenishment regulates cardiomyocyte senescence and cardiac function in aging.
Longevity Relevance Analysis
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NAD+ replenishment reduces cardiomyocyte senescence and improves diastolic function in the aged male heart. This study addresses a fundamental mechanism of aging (NAD+ decline and cellular senescence) rather than merely treating symptoms, demonstrating that restoring metabolic precursors can mitigate specific age-related cardiac dysfunction.
Angela Falvino, Roberto Bonanni, Calogero Asaro ...
· Musculoskeletal Diseases
· Department of Systems Medicine, "Tor Vergata" University of Rome, Rome, Italy.
· pubmed
Aging is an important risk factor for musculoskeletal disorders such as osteoarthritis, osteoporosis, and sarcopenia. Cellular senescence contributes to age-related tissue deterioration by promoting functional alterations and a pro-inflammatory environment, making senotherapeutic...
Aging is an important risk factor for musculoskeletal disorders such as osteoarthritis, osteoporosis, and sarcopenia. Cellular senescence contributes to age-related tissue deterioration by promoting functional alterations and a pro-inflammatory environment, making senotherapeutics promising strategies to selectively eliminate senescent cells or limit their deleterious effects. Our systematic review synthesized the available preclinical evidence on the efficacy of senotherapeutics in murine models of osteoarthritis, osteoporosis, and sarcopenia, analyzing structural and functional outcomes and the main molecular mechanisms involved in the regulation of cellular senescence. A literature search was conducted in the MEDLINE, Scopus, and Web of Science databases according to PRISMA guidelines, while the methodological quality of the included studies was assessed using the SYRCLE RoB tool. 26 experimental studies were included, of which 15 involved osteoarthritis models, 6 osteoporosis models, and 5 sarcopenic models. Overall, senotherapeutics demonstrated protective effects on musculoskeletal tissues by reducing inflammation and improving the evaluated outcomes through the modulation of pathways associated with cellular senescence. However, the heterogeneity of experimental models, therapeutic protocols, and outcome measures limits the possibility of drawing definitive conclusions. Further studies will be necessary to clarify the molecular mechanisms involved, optimize therapeutic strategies, and promote the translation of experimental evidence into clinical practice.
Longevity Relevance Analysis
(3)
Senotherapeutics demonstrate protective effects on musculoskeletal tissues in murine models by reducing inflammation and modulating cellular senescence pathways. This systematic review synthesizes preclinical evidence supporting the hypothesis that targeting cellular senescence—a fundamental hallmark of aging—can mitigate age-related musculoskeletal disorders, thereby addressing a root cause of aging rather than merely treating symptoms.
Björn Schumacher
· Caloric Restriction
· Institute for Genome Stability in Aging and Disease, Medical Faculty, University Hospital of Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. Electronic address: [email protected].
· pubmed
In this issue of Cell, Grońska-Pęski et al. examine how calorie restriction (CR) affects DNA mutation rates. While CR lowers the accumulation of mutations, this effect does not scale with the degree of lifespan extension. Their work raises important new questions about how CR imp...
In this issue of Cell, Grońska-Pęski et al. examine how calorie restriction (CR) affects DNA mutation rates. While CR lowers the accumulation of mutations, this effect does not scale with the degree of lifespan extension. Their work raises important new questions about how CR impacts the causal mechanisms of aging.
Longevity Relevance Analysis
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Calorie restriction reduces the accumulation of DNA mutations without a corresponding proportional increase in lifespan, suggesting that mutation rate is not the primary causal driver of the lifespan extension observed under CR. This is relevant because it challenges the "mutation accumulation" theory of aging and helps delineate the specific mechanisms by which caloric restriction extends healthspan, distinguishing between DNA damage reduction and other metabolic or signaling pathways.
Franziska Meiners, Daniel Palmer, Roberto A Avelar ...
· Cellular Reprogramming
· Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medical Center Rostock, Rostock 18057, Mecklenburg-Vorpommern, Germany.
· pubmed
Partial reprogramming by cyclic expression of Yamanaka factors has been proposed as a rejuvenation strategy, yet evaluating tissue-specific responses and potential risks remains challenging. Here, we reanalyzed RNA-seq data from the liver, kidney, and spleen of aged mice subjecte...
Partial reprogramming by cyclic expression of Yamanaka factors has been proposed as a rejuvenation strategy, yet evaluating tissue-specific responses and potential risks remains challenging. Here, we reanalyzed RNA-seq data from the liver, kidney, and spleen of aged mice subjected to seven months of partial reprogramming. We used the Adverse Outcome Pathway (AOP) framework to estimate adverse and beneficial signatures, assessed functional changes via gene set enrichment analysis and deconvoluted bulk RNA-seq data to estimate differences in cell type proportion. In the liver and kidney, partial reprogramming suppressed age-activated immune and inflammatory processes, while activating age-suppressed metabolic and catabolic pathways. In the spleen, cell cycle, DNA replication, and DNA damage response programs were prominent, indicative of increased proliferative activity, and cell type deconvolution showed increased proportions of megakaryocyte-erythroid progenitor cells and decreased proportions of natural killer cells, while AOPs flagged a potential risk of sustained genomic and proliferative stress. Based on the existing AOP framework, we did not find any enriched Key Events in the kidney (reprogrammed vs. old). In the liver, AOP analysis identified pathways regulated in opposition to liver steatosis, indicated by activation of nuclear receptor signaling (
Longevity Relevance Analysis
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The paper claims that partial reprogramming via cyclic Yamanaka factor expression reverses age-associated transcriptional signatures in liver and kidney while inducing proliferative stress in the spleen. This is relevant because it directly evaluates the efficacy and safety profile of a leading candidate intervention for biological rejuvenation, providing critical tissue-specific data on the balance between rejuvenation and carcinogenic risk.
Lim, S., Pickering, A. M.
· molecular biology
· The University of Texas Health Science Center at Houston
· biorxiv
Aging alters protein abundance throughout the body, but whether proteomic aging signatures are shared across organs, and how they are represented in RNA, remains unclear. Plasma proteomics does not measure protein abundance directly within individual organs. Here, we developed or...
Aging alters protein abundance throughout the body, but whether proteomic aging signatures are shared across organs, and how they are represented in RNA, remains unclear. Plasma proteomics does not measure protein abundance directly within individual organs. Here, we developed organ-specific proteomic aging clocks for eight mouse organs. The clocks retained age associations across independent cohorts but transferred poorly between organs of the same mice, indicating predominantly organ-specific aging signatures. This organ specificity extended to RNA. Applied to the transcriptomes of the genes encoding each clock's protein features, with protein-derived weights unchanged, the scores retained age associations in independent transcriptomic cohorts, with stronger associations in the corresponding organs. The strength of age associations across molecular layers also differed by organ: in paired analysis, protein scores tracked age more strongly than RNA scores in brain and skeletal muscle, with no statistically detectable difference in kidney, liver or lung, suggesting a greater post-transcriptional contribution to proteomic aging in brain and muscle. In spatial transcriptomes, protein-derived RNA scores rose with age within tissue niches, usually without detectable changes in relative niche abundance. In the brain, white matter and glia-enriched microdomains showed elevated proteomic scores compared to other regions since young age. Together, these findings support organ-specific regulation of proteomic aging and identify molecular remodeling within persistent tissue compartments.
Longevity Relevance Analysis
(3)
The paper demonstrates that proteomic aging signatures are predominantly organ-specific and that protein levels track age more strongly than RNA in brain and muscle, indicating significant post-transcriptional regulation of aging. This is relevant to longevity research as it provides a detailed molecular map of how aging manifests differently across tissues, which is essential for developing targeted interventions that address the specific mechanisms of aging in different organs rather than relying on a single systemic biomarker.
Jin Li, Zhen-He Wang, Jia-Xin Pan ...
· Cognitive Dysfunction
· Department of Basic Innovation Research, Beijing Hospital, National Center or Gerontology; National Clinical Research Center for Gerontology; The Key Laboratory of Geriatrics of NHC; Beijing Key Laboratory of Aging Mechanism and Intervention Research on Aging-Related Diseases; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
· pubmed
Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here...
Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.
Longevity Relevance Analysis
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The paper claims that 8-oxoGTP acts as an endogenous signaling molecule that drives microglial activation and neuroinflammation, thereby accelerating cognitive decline. This is relevant to longevity research because it identifies a specific molecular mechanism linking oxidative stress (a root cause of aging) to neurodegeneration, offering a potential therapeutic target to mitigate age-related brain dysfunction rather than just treating downstream symptoms.
Qingxu Song, Xiaoxue Du, Wenbo Dong ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Department of Spine Surgery, The First Hospital of Jilin University, Changchun, People's Republic of China.
· pubmed
Senolytic vaccines hold promise for eliminating senescent cells, but their efficacy is limited by poor seno-antigen immunogenicity and age-related dendritic cell (DC) dysfunction. Here, we engineered an active biomaterial-enabled bi-adjuvant senolytic nanovaccine (CK5-GC-NV) by c...
Senolytic vaccines hold promise for eliminating senescent cells, but their efficacy is limited by poor seno-antigen immunogenicity and age-related dendritic cell (DC) dysfunction. Here, we engineered an active biomaterial-enabled bi-adjuvant senolytic nanovaccine (CK5-GC-NV) by co-assembling CpG oligodeoxynucleotide with a fusion protein of the seno-antigen Gpnmb and a cationic spider silk protein variant (CK5). Beyond antigen delivery, the CK5 scaffold acts as an intrinsic senomodulator associated with the downregulation of mitotic kinases Aurka/b and a concomitant decrease in senescence-associated PI3K/AKT phosphorylation in DCs. This intervention attenuates aged DC phenotypes, restores antigen cross-presentation, and synergizes with CpG to elicit potent cytotoxic T-lymphocyte responses against senescent targets. Across multiple aging mouse models, CK5-GC-NV immunization orchestrated targeted clearance of Gpnmb
Longevity Relevance Analysis
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The paper claims that a bi-adjuvant nanovaccine using a spider silk protein scaffold can reverse dendritic cell senescence and enhance the immune clearance of senescent cells. This is relevant because it addresses a fundamental barrier to senolytic therapies—age-related immune dysfunction—by targeting the root cause of aging (senescent cell accumulation) rather than just treating downstream metabolic symptoms.
Jiangtian Chen, Fernando G Noriega, ★ Marc Tatar
· Juvenile Hormones
· Department of Evolution, Ecology and Organismal Biology, and The Brown Center on the Biology of Aging, Brown University, Providence, RI 02912, USA.
· pubmed
Insulin-like signaling modulates aging and lifespan in insects. Here, we discuss a novel view of this control: insulin hormone in the adult regulates the production of the sesquiterpenoid juvenile hormone (JH) that in turn acts as the systemic regulator of aging and lifespan. Wor...
Insulin-like signaling modulates aging and lifespan in insects. Here, we discuss a novel view of this control: insulin hormone in the adult regulates the production of the sesquiterpenoid juvenile hormone (JH) that in turn acts as the systemic regulator of aging and lifespan. Work in Drosophila establishes that insulin signaling is allatotropic - it stimulates the production and secretion of JH from the corpora allata. JH then exerts systemic effects on adult survival through its control of specific proteins, translation and proteostasis. The interdependent functions of insulin and JH allow reproduction and longevity to be coupled in many insects or decoupled in social insects with long-lived queens and in some long-lived genetic mutants of Drosophila. Features of these insulin-regulated life history syndromes are also found in the nematode Caenorhabditis elegans. Recognizing the systemic role of JH in aging provides grounds to search for analogous systems in mammals that might modulate human lifespan.
Longevity Relevance Analysis
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The paper proposes that insulin-like signaling regulates aging in insects primarily by stimulating the production of juvenile hormone (JH), which acts as the systemic regulator of lifespan. This is relevant because it identifies a specific hormonal mechanism (insulin-JH axis) that couples reproduction and longevity, offering a comparative framework for identifying analogous systemic regulators of mammalian aging.
Vishnu Suresh Babu, Sayan Ghosh, Sridhar Bammidi ...
· Autophagy
· Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
· pubmed
The retinal pigment epithelium (RPE) sustains lifelong proteostasis under chronic stress, yet how post-mitotic cells activate macroautophagy/autophagy when canonical kinase pathways suppress it remains unresolved. Here we demonstrate that AKT1 (protein kinase B alpha), drives aut...
The retinal pigment epithelium (RPE) sustains lifelong proteostasis under chronic stress, yet how post-mitotic cells activate macroautophagy/autophagy when canonical kinase pathways suppress it remains unresolved. Here we demonstrate that AKT1 (protein kinase B alpha), drives autophagy through a non-canonical transcriptional mechanism triggered by isoform imbalance. In RPE and age-related macular degeneration (AMD) models, AKT2 (protein kinase B beta) hyperactivation destabilizes MTORC2 (mechanistic target of rapamycin complex 2) and engages RPS6KB/S6K (ribosomal protein S6 kinase beta) -mediated IRS-1 (insulin Receptor Substrate 1) inhibition, creating a feedforward autophagic arrest. Compensatory AKT1 activation via MTORC2 phosphorylates TERT (telomerase reverse transcriptase) at serine 824, driving nuclear translocation that is independent of telomere maintenance. In the nucleus, TERT assembles with FOXO3 (forkhead Box O3) and MYC (MYC proto-oncogene, bHLH transcription factor) into a tripartite transcriptional complex that occupies the
Longevity Relevance Analysis
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AKT1 phosphorylates TERT at serine 824 to drive a FOXO3-MYC transcriptional complex that restores autophagy in post-mitotic RPE cells. This paper is relevant because it identifies a novel, non-canonical mechanism for maintaining proteostasis and cellular health in post-mitotic tissues, which is a fundamental requirement for extending healthy lifespan and preventing age-related degenerative diseases like AMD.
Ji-Hoon Lee, Sung-Hee Kim, Eun-Kyoung Kim ...
· Current biology : CB
· School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
· pubmed
Cellular turnover is a fundamental biological process that counteracts aging by activating stem cells to replace aging cells. This process is especially critical for maintaining the intestinal epithelium, one of the most rapidly renewing tissues in the body. However, the replacem...
Cellular turnover is a fundamental biological process that counteracts aging by activating stem cells to replace aging cells. This process is especially critical for maintaining the intestinal epithelium, one of the most rapidly renewing tissues in the body. However, the replacement of aging enterocytes cannot be explained solely by the generation of new cells from intestinal stem cells (ISCs); it also requires the complementary process of physically removing aging enterocytes through shedding. Compared with the well-characterized regulation of ISCs, the mechanisms governing enterocyte shedding remain poorly understood. Here, we identify pileup, a novel age-associated antimicrobial peptide (AMP) in Drosophila, as both a genetic marker and a key regulator of enterocyte shedding. Reactive oxygen species (ROS) generated through age-related mitochondrial dysfunction, a process facilitated by Autophagy-related gene 1 (ATG1) kinase, activate hypoxia-inducible factor 1α, which induces pileup expression specifically in aging enterocytes. Pileup then compromises the membrane of these cells and triggers c-Jun N-terminal kinase (JNK) activation, which we propose promotes their shedding. Notably, pileup has three homologs, and loss of all four genes leads to tumorous cell accumulation, gut barrier dysfunction, microbiome dysbiosis, and premature death. Our findings reveal a previously unrecognized role for AMPs in the turnover of aging host cells, extending their classical function beyond microbial defense. This work provides new mechanistic insights into enterocyte shedding and underscores its essential role in preserving gut homeostasis during aging.
Longevity Relevance Analysis
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The paper claims that the antimicrobial peptide pileup, induced by age-related mitochondrial ROS, promotes the shedding of aging enterocytes to maintain gut homeostasis. This is relevant to longevity research as it identifies a specific molecular mechanism for cellular turnover and tissue maintenance in the aging gut, addressing how the body actively removes damaged cells to prevent dysfunction and extend healthspan, rather than merely treating symptoms of age-related disease.
Linggao Liu, Ruiyun Wu, Ziwu Gao ...
· The Journal of nutrition
· Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Laboratory of Processing Technology Integration for Chinese-style Meat and Vegetable Dishes, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
· pubmed
Food-derived protein hydrolysates frequently contain both collagen-associated hydroxyproline (Hyp) and branched-chain amino acids (BCAAs), but the biological consequences of their combination remain unclear. This study tested whether Hyp changes the effects of leucine (Leu), isol...
Food-derived protein hydrolysates frequently contain both collagen-associated hydroxyproline (Hyp) and branched-chain amino acids (BCAAs), but the biological consequences of their combination remain unclear. This study tested whether Hyp changes the effects of leucine (Leu), isoleucine (Ile), and valine (Val) on lifespan and healthspan-related phenotypes in Caenorhabditis elegans and whether these treatment effects are accompanied by coordinated microbial and metabolic remodeling. Amino acid concentrations that did not strongly disrupt bacterial food clearance were selected for lifespan, stress-resistance, motility, muscle-integrity, biochemical, microbiome, metabolomic, and transcriptomic analyses. Hyp+BCAA combinations improved lifespan- and healthspan-related phenotypes in a BCAA- and dose-dependent manner. The strongest combined treatments enhanced resistance to thermal and oxidative stress, preserved age-associated motility and muscle structure, reduced oxidative and lipofuscin-associated markers, and increased ATP-related readouts. Multi-omics profiling showed that these direct treatment effects were accompanied by distinct C. elegans-associated microbiota signatures, altered NAD precursor-related metabolites including nicotinic acid ribonucleoside (NaR), and a Leu+Hyp transcriptional response enriched for energy metabolism, proteostasis, and extracellular-matrix remodeling. Integrated microbiome-metabolome analysis identified a positive association between Rhodococcus abundance and NaR levels. These findings demonstrate that, under the tested culture conditions, Hyp+BCAA exposure improves longevity-related phenotypes and identifies microbial composition, NAD precursor metabolism, and host energy homeostasis as candidate, testable mediators.
Longevity Relevance Analysis
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The paper claims that the combination of hydroxyproline and branched-chain amino acids extends lifespan and healthspan in C. elegans by modulating NAD precursor metabolism and the microbiome. This is relevant because it investigates specific dietary interventions that extend lifespan and identifies potential metabolic mediators (NAD precursors) of aging, although the study is limited to a model organism and represents an incremental advance in nutritional gerontology rather than a fundamental breakthrough.
Mingyang Yi, Minghao Li, Haixia Li ...
· Experimental gerontology
· Department of Respiratory Medicine, Henan Province Hospital of Traditional Chinese Medicine (the Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou, 450003, China.
· pubmed
To evaluate whether intervention-induced changes in epigenetic clocks correspond to changes in clinical outcomes in human geroscience intervention studies.
To evaluate whether intervention-induced changes in epigenetic clocks correspond to changes in clinical outcomes in human geroscience intervention studies.
Longevity Relevance Analysis
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The paper tests the claim that changes in epigenetic clock age are concordant with changes in clinical health outcomes in human geroscience intervention trials. This is relevant because it evaluates the validity of epigenetic clocks as surrogate biomarkers for interventions aimed at slowing or reversing the biological aging process, which is a core objective of longevity research.
Valeria Pellegrini, Rosalba La Grotta, Alessia Metallo ...
· MedComm
· IRCCS MultiMedica Milan Italy.
· pubmed
Leptin, a proinflammatory adipokine, contributes to the chronic low-grade inflammation seen in obesity, but its role in age-related inflammation, that is inflammaging, has been poorly studied. We thus tested the effect of blocking leptin receptor (LEP-R) binding in five models of...
Leptin, a proinflammatory adipokine, contributes to the chronic low-grade inflammation seen in obesity, but its role in age-related inflammation, that is inflammaging, has been poorly studied. We thus tested the effect of blocking leptin receptor (LEP-R) binding in five models of inflammaging, that is replicative senescent endothelial cells, hyperglycemia-treated macrophages or endothelial cells, lipopolysaccharide (LPS)-exposed macrophages, and TCR-stimulated CD4+ T cells. In endothelial cells, leptin enhanced senescence, while leptin neutralization suppressed the senescence-associated secretory phenotype, two effects mediated in part by the mTOR pathway. In both macrophages and endothelial cells, leptin blockade blunted hyperglycemia-induced inflammation, while in macrophages, it also suppressed the LPS-induced senescent and proinflammatory phenotype. In T cells, leptin neutralization produced divergent effects, attenuating the expression of inflammatory and senescence markers in conventional T cells but not in regulatory T cells. To assess translational relevance, we measured leptin and inflammaging markers in plasma samples from two independent cohorts, one of healthy individuals (
Longevity Relevance Analysis
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Leptin neutralization attenuates the senescence-associated secretory phenotype and inflammation in endothelial and immune cell models via mTOR pathway modulation. This paper is relevant because it investigates a specific molecular mechanism (leptin signaling) driving inflammaging and cellular senescence, which are core hallmarks of aging, rather than merely treating downstream symptoms of age-related diseases.
Xiang Li, Hui Shang, Nana Chen ...
· Caenorhabditis elegans
· College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
· pubmed
Ginsenoside Rg1, the main active component of Panax ginseng, has been shown to improve mitochondrial function and delay cell aging by regulating chaperone-mediated mitophagy. However, how Rg1 works in Caenorhabditis elegans is still unclear. In this study, C. elegans was used as ...
Ginsenoside Rg1, the main active component of Panax ginseng, has been shown to improve mitochondrial function and delay cell aging by regulating chaperone-mediated mitophagy. However, how Rg1 works in Caenorhabditis elegans is still unclear. In this study, C. elegans was used as a model to study how Rg1 regulates autophagy and mitochondrial function, and to understand its anti-aging mechanism. The results showed that Rg1 treatment significantly kept cells alive and maintained muscle shape in aged C. elegans, and effectively extended their lifespan. Further studies found that Rg1 improved mitochondrial function by activating mitophagy, which helped the C. elegans better resist oxidative stress. In addition, by combining RNA sequencing and bioinformatics analysis, the transcription factor daf-16 was identified as a key target of Rg1. Experiments using daf-16 knockout strains confirmed that Rg1 produced its anti-aging effects through the daf-16 pathway, in which the activation of mitophagy and the improvement of antioxidant ability were both mediated by daf-16. In conclusion, this study shows that Rg1 slows aging in C. elegans through a daf-16-mediated mitophagy pathway, providing experimental support for the study and use of natural products in anti-aging research.
Longevity Relevance Analysis
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Ginsenoside Rg1 extends the lifespan of C. elegans by activating the DAF-16 transcription factor to promote mitophagy and improve mitochondrial function. This is a standard pharmacological study in a model organism that confirms a known pathway (DAF-16/FOXO) for a natural compound, representing an incremental advance rather than a novel mechanism or breakthrough in longevity science.
Maeyens, L. T., jiang, n., Xu, Z. ...
· physiology
· University of Texas at San Antonio
· biorxiv
Men live shorter lives than women across nearly all human populations, a disadvantage that extends across most biological causes of death and that cannot be fully explained by behavioral or environmental differences. This suggests that fundamental biological mechanisms contribute...
Men live shorter lives than women across nearly all human populations, a disadvantage that extends across most biological causes of death and that cannot be fully explained by behavioral or environmental differences. This suggests that fundamental biological mechanisms contribute to elevated male mortality. Our previous work implicated testicular factors as a major contributor, showing that prepubertal castration extends male lifespan to that of females in UM-HET3 mice, a genetically heterogeneous stock. However, it remains unknown when testicular factors begin to exert their detrimental effects on mortality. Here, we castrated UM-HET3 males before puberty (20 days), after puberty (60 days), or immediately before the typical rise in male mortality (240 days). Castration at all three ages prevented the early male mortality and increased median lifespan by 19.3%, 25.8%, and 32.9%, respectively. The comparable survival benefits of prepubertal and postpubertal castration indicate that exposure to the pubertal surge in testicular factors, including male sex hormones, is not responsible for establishing the male longevity disadvantage. Remarkably, castration at 240 days not only preserved the survival benefit of earlier castration but produced significantly greater survival than earlier castration, suggesting that testicular exposure before 240 days is actually beneficial. The immediate prevention of excess male mortality following castration at 240 days also indicates that the responsible testicular factors act rapidly and that their continued presence is necessary to sustain elevated male mortality. Longitudinal body-composition measurements further revealed that castration shifted males toward a female-like phenotype, characterized by reduced lean mass and continued fat accumulation into later life. Our findings reveal opposing age-dependent effects of testicular factors on survival and narrow the potential therapeutic window to later adulthood.
Longevity Relevance Analysis
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The paper demonstrates that testicular factors have opposing age-dependent effects on male survival, with early exposure being beneficial and late exposure driving excess mortality. This is highly relevant to longevity research as it identifies a specific, modifiable biological mechanism (testicular factors) that contributes to the sex gap in lifespan and suggests that interventions targeting these factors in later adulthood could significantly extend male lifespan.