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
(3)
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
(6)
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
(5)
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
(4)
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
(4)
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
(4)
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
(3)
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
(4)
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
(3)
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
(2)
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
(6)
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.
Zhimin Zhang, Zhiqing Cai, Shencai Liu ...
· Cell metabolism
· Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, Guangdong, China; State Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China.
· pubmed
Physical activity promotes health primarily by decelerating the aging process. Bone is one of the tissues capable of sensing mechanical force and can adapt to different physical demands. However, its role in whole-body aging is unknown. We found that reduced mechano-sensing in os...
Physical activity promotes health primarily by decelerating the aging process. Bone is one of the tissues capable of sensing mechanical force and can adapt to different physical demands. However, its role in whole-body aging is unknown. We found that reduced mechano-sensing in osteocytes, caused by deletion of the mechanosensory channel, Piezo1, accelerated whole-body aging in mice. Dynamic tibial axial loading (DTAL) in mice at 20-24 months of age extended both healthspan and lifespan (9.4%/79.5 days). Furthermore, DTAL reversed bone marrow immunosenescence and induced anti-aging and protective factors while downregulating pro-aging and pro-inflammatory factors. We also identified pigment epithelium-derived factor (PEDF) as a novel mechano-responsive anti-aging factor that is highly associated with healthy aging in humans. Thus, our findings highlighted an essential role for bone mechano-sensing in whole-body aging. This could potentially be manipulated to prevent aging, extend health, and aid those unable to exercise or with decreased mobility.
Longevity Relevance Analysis
(7)
Deletion of the mechanosensory channel Piezo1 in osteocytes accelerates whole-body aging, while dynamic tibial loading extends lifespan and healthspan by inducing anti-aging factors like PEDF. This is highly relevant because it identifies a specific, non-exercise-dependent mechanism (bone mechano-sensing) that regulates systemic aging, offering a potential therapeutic target for individuals who cannot exercise.
Chenyang Guan, Seungjin Ryu, Mingze Dong ...
· Cell
· Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
· pubmed
Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Furt...
Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Further elevating taurine in aged mice enhances health span, engaging anti-inflammatory pathways previously linked to youthfulness, and reduces mortality from sepsis and inflammasome-mediated inflammation, suggesting an enantiostatic response. Mechanistically, diverse NLRP3-specific "danger signals" induce taurine efflux from macrophages as a proximal step to activate the inflammasome and the resultant pyroptosis. Taurine restoration in macrophages prevents NLRP3-induced trans-Golgi network disassembly, thereby suppressing NLRP3 inflammasome activation. Conversely, lowering taurine biosynthesis combined with reduced bioavailability in macrophages exacerbated inflammasome activation. In humans, sustained caloric restriction elevates adipose tissue taurine and is accompanied by lower inflammation. Together, we identify taurine as an immunometabolic rheostat that links danger sensing to NLRP3 inflammasome activation, suggesting taurine-based strategies to alleviate inflammaging and inflammasomopathies.
Longevity Relevance Analysis
(7)
Taurine acts as an immunometabolic rheostat that suppresses NLRP3 inflammasome activation by preventing trans-Golgi network disassembly, thereby reducing inflammaging and extending health span. This paper is highly relevant because it identifies a specific molecular mechanism by which a common metabolite regulates the core inflammatory processes driving aging (inflammaging) and demonstrates that modulating this pathway can extend health span and reduce mortality in aged models, addressing a root cause of age-related decline rather than just treating symptoms.
Craparotta, I., Barbera, M. C., Cassanmagnago, G. A. ...
· cell biology
· Institute of Oncology Research (IOR)
· biorxiv
Throughout life, somatic cells must preserve their identity while retaining the capacity to adapt. How this balance shifts with ageing and rejuvenation remains unclear. Here we identify miR-29 as a central point of convergence between the transcriptional programmes of physiologic...
Throughout life, somatic cells must preserve their identity while retaining the capacity to adapt. How this balance shifts with ageing and rejuvenation remains unclear. Here we identify miR-29 as a central point of convergence between the transcriptional programmes of physiological ageing and two routes to rejuvenation: induced reprogramming and the natural reset of early development. miR-29 rises with ageing, falls in both rejuvenation settings and shows the most conserved age-associated increase across vertebrates. miR-29 inhibition opposes transcriptional ageing, whereas mimics promote an older transcriptional state. Methylome analysis reveals a broader function: inhibition releases the miR-29 brake on remodelling, and mimic treatment reinforces it. This release increases methylation at repeat-associated CpGs and lowers epigenetic-clock estimates through unequal contributions in opposite directions. Inhibition also amplifies stimulus-induced methylation changes but reduces fidelity to lineage-specific methylation patterns. We extend this relationship to cancer, where low miR-29 expression marks tumours with younger epigenetic-age estimates yet greater methylation divergence from their tissue of origin. These findings identify miR-29 as a control point linking ageing, rejuvenation and cancer, and support a maladaptive trade-off model in which epigenetic fidelity is preserved at the expense of the plasticity needed for methylome maintenance and adaptation.
Longevity Relevance Analysis
(6)
The paper claims that miR-29 acts as a central regulator that trades youthful epigenetic plasticity for fidelity, and that inhibiting it can reverse transcriptional and epigenetic aging markers. This is highly relevant to longevity research as it identifies a specific molecular mechanism (miR-29) that drives the aging process and demonstrates that its inhibition can induce rejuvenation, offering a potential target for anti-aging interventions.
Krieger, M. S., Milanova, D., Thompson, D. ...
· systems biology
· Medici Therapeutics
· biorxiv
In the past hundred years, the fraction of fatalities due to age-related disease has risen from an envied minority of cases to the leading cause of death and economic morbidity in the developed world. Despite notable advances in understanding aging, its intrinsic complexity has p...
In the past hundred years, the fraction of fatalities due to age-related disease has risen from an envied minority of cases to the leading cause of death and economic morbidity in the developed world. Despite notable advances in understanding aging, its intrinsic complexity has prevented major therapeutic breakthroughs. This complexity extends across all systems and scales in an organism, leaving a "fingerprint of aging" across every aspect of cell and tissue behavior whose interrelationships are difficult to untangle. Compounding this problem, human aging is observed largely through cross-sectional rather than longitudinal data. Whether such data retain sufficient dynamical information to reveal causal interactions is unclear. Here we show that they can. Using convergent cross mapping (CCM), a method for identifying causal interactions in nonlinear dynamical systems, we reconstruct directed genetic interactions from age-ordered, cross-sectional transcriptomic data - recovering dynamics from populations rather than individuals. Applied to dermal fibroblasts from 490 GTEx donors, CCM identifies a genome-scale causal network whose topology, together with age-dependent changes in gene expression, predicts candidate drivers of aging. We tested these predictions experimentally by single-gene overexpression in fibroblasts from 55-year-old donors. Single-cell RNA sequencing confirmed 53.8% of testable CCM-predicted causal interactions, showing that dynamics reconstructed from cross-sectional populations contain experimentally recoverable information about gene-gene interactions. This 53.8% additionally exceeded that produced by multiple comparanda methods and a random null. We then asked whether this information could identify interventions that reverse cellular aging. Independent transcriptomic and high-dimensional morphological assays show that CCM-selected perturbations shift old fibroblasts toward states characteristic of young cells. These two measures of rejuvenation are strongly correlated, and the strongest interventions cause a majority of 55-year-old cells to resemble cells from 25-year-old donors. Thus, causal dynamics can be recovered from cross-sectional population data and used to identify interventions in aging. More generally, the results suggest a way to distinguish genes that change with age from genes that drive those changes, providing experimentally testable targets for altering the aging phenotype.
Longevity Relevance Analysis
(6)
The paper claims that causal genetic interactions driving aging can be inferred from cross-sectional population transcriptomic data using convergent cross mapping, and that perturbing these identified causal drivers can reverse cellular aging phenotypes. This is highly relevant to longevity research because it moves beyond correlational aging studies to identify causal drivers of the aging process and provides a validated method for discovering interventions that reverse cellular age, directly addressing the root causes of aging rather than just treating symptoms.
Kyle Feola, Peter M Douglas
· Longevity
· Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
· pubmed
The steroid hormone dafachronic acid may carry the effects of reduced mTOR activity between tissues to coordinate metabolism and longevity across the body.
The steroid hormone dafachronic acid may carry the effects of reduced mTOR activity between tissues to coordinate metabolism and longevity across the body.
Longevity Relevance Analysis
(3)
Dafachronic acid acts as a systemic signal that transmits the effects of reduced mTOR activity to coordinate metabolism and extend lifespan. This paper is relevant because it identifies a specific hormonal mechanism that mediates the systemic benefits of mTOR inhibition, a well-established pathway for longevity, thereby advancing the understanding of how tissue-specific interventions can be coordinated to extend healthspan.
Matthew Peloquin, Hubert C Chen, Celine-Lea Halioua-Haubold
· GeroScience
· Loyal Animal Health, San Francisco, CA, USA. [email protected].
· pubmed
The growing evidence that existing cardio-renal-metabolic therapies, such as GLP-1 receptor agonists and SGLT2 inhibitors, confer all-cause mortality benefits has positioned them as the first wave of potential gerotherapeutics. However, repurposing these drugs for a lifespan exte...
The growing evidence that existing cardio-renal-metabolic therapies, such as GLP-1 receptor agonists and SGLT2 inhibitors, confer all-cause mortality benefits has positioned them as the first wave of potential gerotherapeutics. However, repurposing these drugs for a lifespan extension indication remains constrained by trial duration, misaligned incentives, and the lack of a viable regulatory path. We highlight two parallel strategies to address these barriers: (1) identifying and validating precise surrogate endpoints, and (2) modifying the 505(b)(2) pathway to allow accelerated approval of already-approved drugs with demonstrated mortality benefit and favorable post-marketing safety. Veterinary medicine's expanded conditional approval framework already applies these strategies, offering precedent for human gerotherapeutics development.
Longevity Relevance Analysis
(3)
The paper claims that veterinary medicine's conditional approval framework provides a viable regulatory precedent for accelerating the approval of repurposed cardio-renal-metabolic drugs as human gerotherapeutics. This is a policy and regulatory analysis rather than a biological discovery, offering a strategic pathway to overcome trial duration and incentive barriers for existing drugs, but it does not provide new mechanistic insights into the root causes of aging.
Jee Hee Yoon, Ye Hyang Kim, Duyeol Kim ...
· Mitochondria
· Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
· pubmed
Cellular senescence is characterized by coordinated disruptions in mitochondrial function and epigenetic regulation, with perturbation of the mitochondria-chromatin axis emerging as a central hallmark of this process. Resveratrol (RSV) has been extensively investigated as a modul...
Cellular senescence is characterized by coordinated disruptions in mitochondrial function and epigenetic regulation, with perturbation of the mitochondria-chromatin axis emerging as a central hallmark of this process. Resveratrol (RSV) has been extensively investigated as a modulator of this axis; however, its clinical utility is constrained by dose-dependent cytotoxicity. Here, we evaluated the safety profile and anti-aging potential of resveratrol glucoside (R-glc), a glucosylated derivative of RSV. R-glc exhibited markedly reduced cytotoxicity compared to RSV and effectively attenuated multiple senescence-associated phenotypes at low concentrations. Mechanistically, R-glc enhanced mitochondrial function, as evidenced by increased oxidative phosphorylation and reduced glycolytic dependence. At the epigenetic level, R-glc upregulated the NAD
Longevity Relevance Analysis
(2)
Resveratrol glucoside (R-glc) alleviates senescence-associated phenotypes in vitro by coordinating mitochondrial function and chromatin structure with reduced cytotoxicity compared to resveratrol. This is an incremental advance in the field of geroprotectors, offering a potentially safer derivative of a known compound, but it lacks the novelty or in vivo validation required for high impact.