Abstract

Assessment of biological aging using proteomic clocks may enhance risk prediction and elucidate the molecular links between aging and chronic diseases. Here, among 17,473 participants of the European Prospective Investigation into Cancer and Nutrition, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with risk factors, 24 incident chronic diseases and all-cause mortality, over up to 28 years of follow-up. Replication was conducted in the Whitehall II study. We show that the global age gap, an age acceleration score combining proteomic clocks, was associated with smoking, alcohol consumption, physical inactivity and higher risk of mortality, cardiovascular diseases, dementia and cancers of the liver, upper aero-digestive tract, lung and kidney. Lung, kidney and stomach cancers were more strongly associated with related organ-specific age gaps. Predictive performance of proteomic clocks for mortality was comparable to that of classical lifestyle risk factors. In summary, proteomic clocks appear promising biomarkers of generalized age-related disease risk.

Abstract

Mitochondria, multifunctional organelles that regulate cellular energy metabolism and signaling pathways, play a pivotal role in maintaining the physiological functions of the gut and kidneys, as well as influencing the progression of chronic kidney disease (CKD). Through the gut-kidney crosstalk, gut microbiota modulate gut and renal pathophysiology and also influence mitochondrial activity in intestinal and renal cells. This review explores the regulatory roles of mitochondria in preserving epithelial barrier integrity, regulating intestinal metabolism, and maintaining gut microbiota homeostasis. It also examines the contributions of mitochondrial biogenesis, dynamics, autophagy abnormalities, and mitochondrial DNA (mtDNA) damage to renal pathological progression. Moreover, we highlight the bidirectional interactions between intestinal and renal mitochondria via the microbiota-mitochondria-kidney axis and mechanisms involving inflammation, oxidative stress, and ferroptosis. Therefore, targeting mitochondrial regulation through non-pharmacological interventions such as dietary adjustments, probiotic supplementation and fecal microbiota transplantation (FMT) emerges as a promising therapeutic strategy for maintaining renal health by optimizing mitochondrial function. In conclusion, elucidating the mechanisms of mitochondrial involvement in the gut-kidney axis will lay the foundation for novel therapeutic approaches to CKD and other gut-kidney axis-related disorders.

Abstract

The interplay between gut microbiota and mitochondria represents a dynamic relationship that profoundly impacts host physiology, ranging from maintaining intestinal homeostasis to regulating systemic metabolic and neurological functions. Microbial metabolites such as short-chain-fatty-acids, bile acids, and amino acid derivatives serve as pivotal modulators of mitochondrial bioenergetics, oxidative stress management, and fission–fusion processes. These interactions are vital for preserving epithelial integrity, supporting energy metabolism, shaping immune responses, and managing inflammatory signaling pathways. Disruptions within this microbiota–mitochondria axis are associated with various pathologies, including non-alcoholic fatty liver disease, obesity, type 2 diabetes, and chronic inflammatory conditions like inflammatory bowel disease. Additionally, growing evidence connects gut dysbiosis and mitochondrial dysfunction to neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, highlighting the importance of this bidirectional relationship in maintaining neuronal health. On a mechanistic level, pathways involving AMPK, sirtuins, and PGC-1α govern mitochondrial biogenesis and adaptive responses to microbial signals. Dysregulation of these pathways can heighten oxidative stress, hinder mitophagy, and contribute to systemic inflammation. Emerging therapeutic strategies aim to target this axis through dietary modifications, probiotics and engineered microbes, FMT, and mitochondria-specific pharmacological treatments. These interventions focus on restoring metabolic stability, enhance resilience against oxidative damage, and slowing disease progression. By integrating insights from fields such as metabolism, immunology, and neuroscience, this review positions the microbiota–mitochondria axis as a critical area of focus in biomedical research. A deeper understanding of this communication network offers promising opportunities for precision therapies aimed at addressing metabolic, inflammatory, and neurodegenerative diseases.

Abstract

Cardiolipin (CL) is a four-acyl chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-acyl chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of IMM structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

https://journals.lww.com/nsca-jscr/abstract/9900/moderate_intensity_resistance_training_with.1095.aspx

Abstract

McMahon, G, Morse, C, Burden, A, Winwood, K, and Onambele–Pearson, G. Moderate intensity resistance training with partial range-of-motion at long muscle lengths elicits similar hypertrophy and architectural adaptations as high intensity resistance training using full range-of-motion. J Strength Cond Res XX(X): 000–000, 2026—Resistance training (RT) elicits varying magnitudes of active and passive forces in muscle. Evidence is lacking comparing chronic RT outcomes including muscle thickness (MTH) and muscle architecture (fascicle length [Lf], pennation angle [pen]) performing training at shorter, longer, and full ranges-of-motion (ROM). A total of 45 subjects were randomly assigned to 1 of 4 groups—shortened partial ROM (SP, 0–50° knee flexion, 80% 1 repetition maximum [1RM]), lengthened partial ROM (LP, 40–90° knee flexion, 55% 1RM), full ROM (FROM, 0–90° knee flexion, 80% 1RM), or control (CON)—completing 8 weeks of knee extensor exercise. Vastus Lateralis MTH, PEN, and Lf were measured at 25, 50, and 75% femur length pre–post training and analyzed as delta (Δ) change (%); statistical significance was set at p < 0.05. ΔMTH was greater in LP and FROM (p < 0.05) vs. SP at 75%. ΔMTH LP was greater than SP at 25% (p < 0.05) and ΔMTH FROM was greater than SP at 50% (p < 0.05) with no differences between LP and FROM at any location. ΔLf was greater in LP vs. FROM (p < 0.05) at 25 and 75%, and LP vs. SP (p < 0.05) at all sites. ΔLf was greater in FROM vs. SP (p < 0.05) at 50 and 75%. Absolute and normalized baseline Lf was inversely correlated with ΔLf in all groups (p < 0.001). This study provides novel evidence that moderate-intensity RT with partial ROM at long muscle lengths elicits similar hypertrophic and superior Lf adaptations as high-intensity full ROM training. These findings challenge traditional RT prescription, offering new insights for optimizing muscle size and architecture in athletic populations.

Highlights

•Psychological stress induces aging-like dysfunction in HSCs

•mPFC/PAG suppression impairs HSCs through sympathetic gut signaling

•Stress reduces L. reuteri and spermidine to promote ferroptotic stress in HSCs

•Spermidine restores autophagy and HSC function under psychological stress

Summary

Chronic stress influences hematopoietic stem cells (HSCs). However, how psychological stress regulates HSC function remains incompletely understood. Here, we show that psychological stress impairs HSC self-renewal and lymphoid differentiation, inducing aging-like phenotypes. Stress suppresses neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG), leading to HSC dysfunction, whereas chemogenetic activation of these regions restores HSC function. Psychological stress or chemogenetic inhibition of the mPFC and PAG reduces the abundance of L. reuteri in the gut microbiota and lowers spermidine levels. Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs. We further demonstrate that mPFC and PAG activity regulate the intestinal environment through a sympathetic pathway, reducing intestinal mucin levels, L. reuteri abundance, and spermidine levels. These findings identify a brain-gut-bone marrow axis linking psychological stress to aging-like HSC dysfunction through sympathetic regulation of intestinal microbiota and spermidine metabolism.

Abstract

Life on Earth has evolved in a form suitable for the gravitational force. Although the pivotal role of gravity in gene expression has been suggested, the molecular details remain unclear. Here, we show that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling reveals reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under microgravity. We found that attenuation of cell adhesion through laminin–integrin interactions caused the phenotype. Mitochondrial translation is activated by a signal relayed by FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and the mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix. Consumption of mitochondrial malonyl-CoA by mtFAS reduces the malonylation of the translational machinery and accelerates the rates of translational initiation and elongation. Physiologically, this system operates in mechano-response of skeletal muscles. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in mitochondria.

Abstract

Background: 

Pancreatic beta cells must rapidly escalate protein synthesis to maintain systemic glucose homeostasis. While the transcriptional responses are well characterized, the immediate translational dynamics governing this adaptive phase remain poorly defined.

Methods: 

We performed high-resolution ribosome profiling (Ribo-seq) on primary mouse islets under acute low-glucose (2.5 mM) and high-glucose (25 mM) conditions and integrated analysis of the differential translation, functional enrichment, translational efficiency (TE), and ribosome kinetics. The protein levels and mRNA expression were validated using Western blot and quantitative PCR (qPCR), respectively.

Results: 

We identified extensive translational reprogramming involving 1, 680 differentially translated genes. High glucose triggered a significant upregulation of immediate early genes (e.g., Fos and Nr4a1) and a concurrent inhibition of stress-related genes (e.g., Ddit3 and Trib3). On the other hand, beta cells prioritized the synthesis of cytosolic ribosomal proteins and elongation factors to expand the biosynthetic machinery. This was coordinated with a scale-up of the downstream secretory pathway (e.g., Sec61a1) and a metabolic realignment, characterized by the translational upregulation of mitochondrial enzymes (e.g., Cs and Fh1) despite the relative suppression of mitochondrial biogenesis genes. Furthermore, TE analysis revealed that several genes were regulated independent of their mRNA levels, such as Rpl3 and Atf4. Finally, kinetic analysis suggested that high glucose affected the ribosome occupancy density and distribution on specific transcripts, such as Ins1.

Conclusion: 

Our research characterizes the translatome as a dynamic regulator of the glucose response. By revealing these rapid translational nodes, we provide potential targets to restore the insulin synthetic capacity and secretory function in T2DM, offering a mechanistic framework for the development of therapies centered on preserving β-cell proteostasis.

Highlights

• • Systemic recalibration and epigenetic resetting target different constraints in ageing.
• • Blood rejuvenation is increasingly viewed through dilution of inhibitory age-elevated signals.
• • Partial reprogramming addresses intracellular ageing mechanisms at the epigenetic level.
• • Disease context may determine whether one strategy or both are required.
• • Future priorities include mechanistic crosstalk and biomarkers for multimodal intervention.

Abstract

Two principal strategies have gained prominence among currently recognised approaches to anti-ageing: systemic interventions that modulate the circulatory environment and cellular interventions that reset epigenetic information. Systemic approaches, beginning with experimental heterochronic parabiosis models that are not applicable to humans and extending to clinically applicable therapeutic plasma exchange, test the hypothesis that ageing is promoted by the accumulation of inhibitory blood-borne factors. Cellular reprogramming, particularly partial reprogramming through transient expression of Yamanaka factors, tests the alternative hypothesis that ageing is primarily a cell-intrinsic process associated with loss of epigenetic information. This perspective critically evaluates these two modalities. The dilution hypothesis is examined together with its limitations and the unresolved complexities of systemic interventions. The challenge of cell-autonomous ageing is also considered, particularly the persistence of cell populations that remain refractory to systemic rejuvenation. A conceptual framework integrating these two axes of ageing is then presented. This framework suggests that combined systemic recalibration and targeted partial reprogramming warrant further investigation as a multimodal approach to ageing intervention. Future research priorities include mechanistic clarification of this systemic-cellular interaction and development of robust biomarkers to evaluate multimodal interventions.

Abstract:

Age-related macular degeneration (AMD) is a leading ocular disorder that causes irreversible visual impairment and blindness in the elderly population. Accumulating evidence demonstrates that AMD is the end-stage outcome of various retinal degenerative lesions and vascular anomalies. Its core pathogenic mechanisms mainly involve dysfunction and atrophy of retinal pigment epithelium (RPE) cells, choroidal capillary degeneration, pathological choroidal neovascularization (CNV), chronic inflammation, oxidative stress injury, deposition of extracellular substances such as drusen, and genetic predisposition. Given its multifactorial origin and complicated pathophysiological processes, the full molecular regulatory network of AMD has not been fully clarified, which restricts the development of more efficient intervention regimens. This review systematically summarizes the latest research progress concerning the molecular mechanisms of AMD, and comprehensively discusses mainstream and emerging therapeutic strategies, including anti-vascular endothelial growth factor (VEGF) drugs, antioxidant and mineral supplements, photodynamic therapy, and laser therapy, as well as innovative modalities such as gene therapy, stem cell therapy, and targeted regulation of complement and inflammatory pathways. It is intended to provide theoretical basis and research references for in-depth mechanistic exploration, early prevention and precise clinical management of AMD.