Myriam Gorospe

Background and Objectives: Physical exercise is widely recognized as an effective non-pharmacological intervention that improves not only functional capacity but also cognition and quality of life in older adults. However, the molecular pathways through which it influences aging-related processes remain incompletely understood. This systematic review and meta-analysis aimed to synthesize current evidence on the effects of structured physical exercise intervention on molecular biomarkers associated with inflammation and oxidative stress in older adults. Research Design and Methods: Randomized controlled trials that included participants ≥65 years old were identified through searches of PubMed, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library. Results: A total of 50 reports (4,379 participants) were included in the qualitative synthesis, and 38 of them in the different meta-analyses performed. Exercise interventions ranged from 8 weeks to 12 months and included aerobic, resistance, and multicomponent training. Pooled analyses indicated modest but significant reductions in C-Reactive Protein (CRP) and high-sensitivity CRP, as well as increases in Interleukin (IL)-10. Effects on other pro-inflammatory cytokines, including IL-6 and TNF-α, were inconsistent across studies. Evidence from a limited number of trials (n = 6) also suggested improvements in redox balance. Discussion and Implications: Overall, structured physical exercise demonstrates a moderate immunomodulatory and antioxidant effect in older adults, although bias was moderate to high. PROSPERO registry: CRD420251006248.

Age-associated hematopoietic skewing results in an increase in the neutrophil-to-lymphocyte ratio, which serves as a strong predictor of all-cause mortality in older adults, although its causes are incompletely understood. Here we show that cytotoxic CD4 ⁺ T lymphocytes accumulate in the bone marrow of mice during aging and induce myelopoiesis, increasing the neutrophil-to-lymphocyte ratio. T cell receptor-dependent induction of mitochondrial stress and activation of STING upregulates the chemokine CCL5 in CD4 ⁺ T lymphocytes. During aging, hematopoietic stem cells and downstream myeloid progenitors upregulate CCR5, the primary receptor for CCL5. Genetic ablation of Ccr5 in hematopoietic progenitors mitigates T cell-induced myeloid skewing and neutrophil expansion. Pharmacological blockade of CCR5 using the Food and Drug Administration-approved drug maraviroc normalizes myelopoiesis, reduces circulating and tissue-infiltrating neutrophils, and improves multiple aging-related biomarkers and functional outcomes in aged mice. Together, these findings demonstrate a T cell–bone marrow axis that exacerbates age-associated decline and highlight CCR5 inhibition as a potential geroprotective strategy.

Subcellular spatial transcriptomics (SSTs) is transforming biology by revealing where individual RNA molecules are located within intact tissues, providing unprecedented insight into how cells function and interact. Achieving this promise depends on accurately identifying the boundaries of individual cells, making cell segmentation one of the field’s central computational challenges. A core methodological issue is how best to ensure correct and biologically accurate assignment of transcripts to cells using cell segmentation algorithms. Recent advances in deep learning models have been instrumental in developing tools to enable more accurate transcript-to-cell maapping across a wider range of tissues and resolutions. Here, we review key features of emerging deep learning-based cell segmentation strategies, including fully convolutional neural networks, transformer-based models, and foundation models, highlighting their architectural innovations, performance characteristics, and practical limitations. We conclude that transformer-based and foundation model-based models have better generalizability and require minimal retraining, but their adoption is limited by larger data requirements and higher computational cost. We predict a larger adoption of these more flexible and robust methods as deep learning architectures become more scalable and improved hardware accessibility permits further advancements of quantitative, high-resolution tissue analysis. We propose that the convergence of biology and artificial intelligence (AI) and the continued innovation in deep learning-based cell segmentation will accelerate method development, standardization, and deployment in both basic biological research and clinical applications.

Circular RNAs are covalently closed RNA molecules mainly generated by spliceosome-dependent back-splicing from multi-exon transcripts. However, this mechanism does not readily explain circular RNAs associated with single-exon loci. Here, we identify circRMRP, an antisense circular RNA complementary to the single-exon noncoding RNA RMRP, as a model for this poorly understood subset of circular RNAs. We find that circRMRP is a bona fide nuclear circular RNA that physically associates with linear RMRP. Its biogenesis requires transcription of RMRP and locus integrity, but is not simply determined by the steady-state abundance of mature RMRP. Mechanistically, circRMRP formation depends on endogenous telomerase reverse transcriptase (TERT), which promotes the production of a self-complementary RMRP-derived RNA species, termed long RMRP. Disruption of the RMRP 3′ region reduces both long RMRP and circRMRP, and their similar decay kinetics support an intermediate role for long RMRP in circRMRP biogenesis. We further identify hnRNPC as a regulator within the endogenous RMRP-TERT axis and RTCB as a candidate downstream processing factor. These findings uncover TERT-dependent complementary RNA synthesis as a previously unrecognized route to circular RNA biogenesis from single-exon loci.

In senescent cells, functional alterations in organelles like mitochondria and lysosomes are well characterized, but senescence-associated changes in Golgi function are not. An RNA interference screen revealed that silencing subunits of the coatomer protein I (COPI) complex, critical for intracellular transport involving the Golgi, reduced extracellular vesicle uptake. In proliferating WI-38 fibroblasts, silencing COPI constituents COPA, COPB1, COPB2, or COPD induced ATF4 production and disrupted autophagy, apoptosis, and cytokine signaling, all hallmarks of impaired Golgi–to–endoplasmic reticulum transport, while silencing COPI constituents COPG1, COPE, or COPZ1 altered the production of extracellular matrix proteins. Furthermore, individual COPI proteins associated with Golgi and endosomal proteins, supporting roles in vesicular trafficking. In senescent WI-38 fibroblasts, silencing COPI proteins did not elicit these phenotypes. Our findings underscore the distinct, multifunctional actions of individual COPI proteins and their key roles in intracellular homeostatic transport networks that become attenuated during senescence.

SUMMARY: Regeneration of skeletal muscle preserves muscle mass and function, which decline with age. Here, we sought to identify long noncoding (lnc)RNAs involved in skeletal muscle myogenesis and potentially relevant to muscle aging. Cross-sectional analysis of skeletal muscle transcriptomes from healthy 22-through 89-year-old individuals revealed lncRNA LANCL1-AS1 among the top declining transcripts. Conversely, LANCL1-AS1 increased robustly during skeletal myogenesis and promoted myogenic differentiation in culture. Affinity pulldown by ChIRP followed by mass spectrometry revealed that LANCL1-AS1 associated with the mitochondrial protein LRPPRC, enhancing the formation of the chaperone complex LRPPRC-SLIRP, which maintains longer poly(A) tails of mitochondrial (mt-)mRNAs and stabilizes mt-mRNAs. Importantly, while myoblasts from old rhesus monkey muscle expressed lower levels of LANCL1-AS1 and mt-mRNAs, and displayed lower mitochondrial activity than young monkey myoblasts, overexpressing LANCL1-AS1 in old myoblasts restored mitochondrial activity and myogenesis. We propose that the age-associated reduction in LANCL1-AS1 contributes to impaired mitochondrial function and reduced myogenic capacity in aging skeletal muscle.

Growth/differentiation factor–15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer’s disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15’s mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses. These findings support circulating GDF15’s role as an early biomarker—particularly for vascular dementia and neuroinflammation—and identify the mechanisms by which it may drive dementia risk.

Cellular senescence is a state of sustained cell cycle arrest triggered by sublethal damage from both intrinsic and extrinsic stresses.1,2 Senescent cells are characterized by altered gene expressi...