Cover legend: The cover image is based on the article 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes by Estevão Scudese et al., https://doi.org/10.1111/acel.70054

Cover legend: The cover image is based on the article A Xanthine Derivative With Novel Heat Shock Protein 90-Alpha Inhibitory and Senolytic Properties by Sandra Atlante et al., https://doi.org/10.1111/acel.70047.

Cover legend: The cover image is based on the article The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging by Muthu Saravanan Manoharan et al., https://doi.org/10.1111/acel.70063.

Cover legend: The cover image is based on the article Identification of Senomorphic miRNAs in Embryonic Progenitor and Adult Stem Cell-Derived Extracellular Vesicles by Tianpeng Zhang et al., https://doi.org/10.1111/acel.70071.

Cockayne Syndrome complementation group B (CS-B) is a highly debilitating progeroid syndrome that often culminates in the death of patients before adulthood. This review explores the pathogenesis of CS-B and proposes that a combination of DNA damage accumulation, transcriptional dysregulation, and mitochondrial dysfunction is its underlying cause.

Graphical summary depicting the changes in the co-receptor landscape (a), migratory potential (b), differentiation program (c) and communication networks (d) in Tregs from the -< 66-year-old cohort versus the 85-year-olds.

This study aimed to find safe senolytic drugs that selectively eliminate senescent cells. Focusing on HSP90 inhibitors, we employed a virtual screening to identify novel, safer compounds (A). K5, a xanthinic candidate, effectively eliminated senescent cells in various cellular models (B), extended lifespan in flies, and reduced aging signs in mice (C). K5's safety profile and multimodal action highlight its therapeutic potential for combating aging and age-related diseases. Created in BioRender. Spadotto, V. (2025) https://BioRender.com/u88m942.

Senolytic therapy restores neurovascular function, blood–brain barrier integrity, and cognitive performance in aged mice by targeting endothelial senescence. Findings highlight that brain microvascular endothelial cells are highly vulnerable to aging-induced senescence, and early intervention in middle age may be the most effective strategy to prevent neurovascular dysfunction and cognitive decline.

5′-tiRNA-His-GTG expression level is upregulated in the photoaging cell model. 5′-tiRNA-His-GTG negatively regulates the expression of NUP98, thereby activating the JNK signaling pathway to regulate cell senescence.

This study demonstrates that aging induces oxidative stress and inflammation in the hematopoietic immune system, resulting in immune homeostasis dysfunction, including alterations in B cells and hematopoietic stem cells, senescent cells (SnCs) accumulation, and senescence-associated secretory phenotypes (SASPs) production. Notably, the study highlights that Pyrroloquinoline Quinone (PQQ), a potent antioxidant, exerts both senolytic and senomorphic effects, effectively reducing oxidative stress and immunosenescence, underscoring its potential for mitigating age-related immune dysfunction.

Multi-ciliated cells in the infundibulum and ampulla (INF/AMP) epithelium are vacuolated in aging. Unique cellular susceptibility of the INF/AMP epithelial population and aging-associated decline in ovarian artery circulation, which supports the ovary and INF/AMP, contribute to this region-specific vacuolation phenotype, as a consequence of a mildly stressed microenvironment.

Alternate day fasting alleviates aging-induced intestinal epithelial barrier damage by regulating mitochondrial metabolism in small intestinal stem cells.

Age-related increases in IGF-1 expression in the skin accelerate stem cell exhaustion and senescence by impairing SIRT1 function, ultimately driving hair follicle aging. Conversely, activating SIRT1, clearing senescent cells, or adopting dietary restriction can mitigate excessive IGF-1 signaling and provide a promising strategy to rejuvenate hair follicle stem cells.

Changes in mitochondrial structure and dynamics during aging provide a mechanism for the development of age-related sarcopenia, a condition characterized by muscle mass loss. Through the creation of three-dimensional models of mitochondria from quadriceps muscle tissue taken from old and young humans, a loss in mitochondrial complexity was observed to occur during aging. A decrease in the expression of mitochondrial fusion protein mitofusin 2 (MFN-2) in older populations may drive these mitochondrial structural changes. A Drosophila model with the MFN-2 ortholog knocked down demonstrated a loss of mitochondrial complexity and lower quality cristae, which parallel changes in mitochondria observed in older humans. The use of an in vitro cell exercise model showed that the mechanism by which exercise counteracts the effects of sarcopenia, age-related disease may be due to increased expression of MFN-2 during exercise.

Our study presents a groundbreaking longitudinal assessment of age-related cognitive decline in a large cohort of aged mice. Through the development of the Cognitive Frailty Index (CoFI), we introduce a robust metric that correlates strongly with advancing age and mortality. Importantly, CoFI and physical frailty are distinct entities, with CoFI offering a new tool to assess cognitive impairment independently from physical decline. This adaptable tool will be valuable for testing the efficacy of innovative interventions in the field of Geroscience.

A comprehensive causal effect analysis was used to illustrate the associations between gut microbiota, aging indicators, and age-related diseases. This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery.

In ADR-induced longevity in C. elegans, neuronal BLI-4 processes neuropeptides, which are then released with the assistance of UNC-31 and GOLG-2.

The underlying mechanisms of age-related revascularization impairment are not clear. Our research firstly identified that macrophages were more senescent in the ischemic skeletal muscle of old mice and senescent macrophages could inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing VEGF-A165B expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index.

A retrospective analysis of the most effective known geroprotectors shows that they act by polypharmacological mechanisms. Using graph neural networks, we predict polypharmacological geroprotectors, validate their polypharmacological mechanisms experimentally, and show them to be exceptionally effective. Thus, it is possible to rationally design polypharmacological geroprotectors with exceptional efficacy.

Exercise improved PD pathology and memory by reducing microglial inflammation, apoptosis, and the formation of the NLRP3 inflammasome via irisin signaling. Irisin administration partially replicated the beneficial effects of exercise on PD pathology.

Dietary restriction mitigates vascular aging in DNA-repair-deficient Ercc1^Δ/− mice by reducing extracellular matrix remodeling, inflammation, oxidative stress, and switching of vascular smooth muscle cells to a macrophage-like phenotype. Our findings suggest that the cGAS-STING pathway plays a key role in vascular aging and that the benefits of dietary restriction may result from reducing its activation. Created in BioRender. Van der pluijm, I. (2025) https://BioRender.com/iwpqncu.

Human aging shows puzzling diversity: similar aging rates yet vastly different health outcomes. Our study of ~17,500 people revealed a health-promoting trait (more common in women) linked to strong immune resilience and high expression of TCF7, a key immune gene. This trait enables individuals to fight infections like COVID-19 more effectively, respond better to vaccines, avoid comorbidities, and live longer. Its decline after age 70 may explain lifespan limits. These findings redefine aging as a tug-of-war between health-promoting (salutogenic) and disease-driving (pathogenic) processes, opening new treatment paths.

Li et al. revealed that aged gut microbiota induces cognitive decline and microglia-mediated synapse loss. Fecal Bifidobacterium pseudolongum abundance was reduced in patients with cognitive impairment and microbiota transplantation from patients with fewer B.p abundance yielded worse cognitive behavior in mice. Supplementation with B.p improves aging-related cognitive decline and prevents microglia engulfment of synapses via activation of IAA/AHR signaling.

Integration of multi-omics analyses reveals PDAP1 as one of the key regulators of longevity and aging. Mendelian randomization, colocalization, prospective studies, and in vitro experiments highlight PDAP1's effects on mortality, lifespan, and cellular senescence.

Autophagy regulates ovarian reserve, with Cathepsin B playing a critical role in aging. Inhibition of Cathepsin B increases follicle count, enhances IGF1R–AKT–mTOR signaling and improves mitochondrial function without compromising fertility. This conserved mechanism suggests potential therapeutic strategies to delay ovarian aging and sustain fertility, offering new insights into reproductive longevity.

Injury then recovery markedly rewires the DNA methylome in aged skeletal muscle.The addition of senolytics during muscle regeneration decelerates DNAmAGE more than regeneration alone as well as targets collagen remodeling and stem cell function-related genes. Regeneration in young adult mice has a less pronounced effect on the methylome-transcriptome landscape than in aged skeletal muscle, but still elicits a distinct molecular profile versus aged skeletal muscle after injury.

Amyloid-β (Aβ) oligomers affect VDAC1 electrophysiology and the physiological metabolic cross-talk between cytosol and mitochondria. The use of a small, synthetic VDAC1-antagonist peptide, derived from hexokinase, restores mitochondrial functionality, and respiration in cellular models of Alzheimer's disease.

Expression of HIRA in embryonic melanoblasts is required for proper epigenetic programing and lineage differentiation. Although HIRA deficiency results in a mild phenotype at birth and young adulthood, the melanocytic lineage is sensitive to proliferative challenge, prone to loss of stem cells and dramatically accelerated hair greying in later life. This shows how early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue-specific stem cells during aging.

A senomorphic miRNA cocktail (E5), consisting of miR-181a-5p, miR-92a-3p, miR-21-5p, and miR-186-5p, was identified from a pool of miRNAs enriched in extracellular vesicles (EVs) derived from multiple functional human stem cell types. E5 reduces senescence and SASP markers both in cell culture and in aged mice. Mechanistically, E5 targets key regulators of the p53 pathway, including PCAF and HIPK2, leading to decreased p53 phosphorylation and acetylation. These effects result in downregulation of p16^INK4a, p21^Cip1, IL-1β, and IL-6 expression, and a reduction in SA-β-gal+ and γ-H2AX+ cells across multiple tissues, indicating the senomorphic potential of E5 for healthspan extension.

RNAge is a transcriptional based computational approach to measure changes in cellular age upon experimental manipulation. In silico screening of a database of transcriptional changes from drug perturbations identified a novel aging agent that was applied to an hPSC model of neurodegenerative disease to trigger a late-onset phenotype.

(A) A previous immunosenescence profile in individuals infected with SARS-CoV2 creates a permissive environment for progression to severe COVID-19: higher inflammaging, accumulation of exhausted/senescent T cells, an oligoclonal B-cell repertoire, and accelerated epigenetic age. (B) Inflammatory profiles of mild COVID-19 and mild flu-like infections are distinct, highlighting the uniqueness of SARS-CoV2 infection.

p62 exhibits diminished expression in aging skin and senescent cells. p62 serves to inhibit the accumulation of USP7 during senescence induction. The Tyr-67 residue within the PB1 domain or Gln-418 within the UBA domain of p62 forms a hydrogen bond with Ala-993 of the Ubl5 domain of USP7.

Schematic diagram illustrating the protective role of protein disulphide isomerase (PDI) against DNA damage via non-homologous end-joining (NHEJ), which repairs double stranded DNA breaks (DSBs). Induction of DNA damage results in the formation of γH2AX and p53-binding protein 1 foci during NHEJ repair of DSBs. PDI (red circles) translocates into the nucleus following damage, where it co-localises at DSB foci, facilitating NHEJ DNA repair. The PDI QUAD (green circles) mutant contains replacement of all four redox-active cysteine residues with serine (SGHS SGHS) and it loses the redox activity but retains the chaperone function of PDI. The QUAD mutant is not protective against DNA damage, demonstrating that the redox activity of PDI is required for its function in NHEJ. Figure created with BioRender.com.

Transcriptomic analyses reveal an age-related decline in autophagy pathways in RPE/choroid. These pathways remain unchanged in early AMD but become bidirectionally dysregulated in later stages, along with increased RPE loss. Pre-treatment with trehalose eyedrops enhances RPE autophagy flux and prevents light-induced outer retinal degeneration in mice (Image created with BioRender.com).

Integrated analysis of bulk-cell and single-cell RNA-seq data from childhood to frailty revealed nonlinear transcriptomic changes in peripheral blood mononuclear cells, marked by dramatic early-life shifts in inflammation, myeloid cells, and lymphocyte features, followed by stability in healthy elderly individuals. In contrast, frail elderly individuals showed disrupted immune profiles, characterized by heightened monocyte-driven inflammation, regulatory T-cell activation, and impaired cytotoxic lymphocyte function.

TFEB dynamics during oxidative stress-induced premature senescence. The tBHP treatment undermines GSH-dependent antioxidant mechanisms, leading to increased ROS production and lysosomal damage. In the stress phase, we observed the concomitant inhibition of Akt along with activation of AMPK, together leading to mTOR inhibition and subsequent dephosphorylation of TFEB which is known to drive its nuclear localization and activation. Inside the nucleus, TFEB activates the transcription of the Coordinated Lysosomal Expression and Regulation (CLEAR) network genes, enhancing lysosomal biogenesis, and antioxidant capacity, thereby promoting lysosomal recovery, autophagy and subsequent entry into the senescent state. Decreased ROS levels restore Akt and AMPK pathways, leading to the resurgence of mTORC1 activity, along with TFEB inactivation as the cells transit into senescence.

The causal relationship between random mtDNA mutations and reduced mitochondrial respiratory activity in premature aging Polg^mut/mut mice remains unclear. This study shows that the abnormal mitochondrial function in Polg^mut/mut mice is more closely associated with the nuclear Polg genotype than with the mtDNA genotype.

Once internalized into endolysosomes, HIV-1 Tat interacts and activates TLR7, causing endolysosome damage. Such interaction between HIV-1 Tat and TLR7 also leads to a senescence-like phenotype in astrocytes, including cell cycle arrest, elevated levels of p21 and p16 proteins, increased SA-β-gal activity, and enhanced secretion of SASP factors.

The figure combines the effects of aging and physical activity on different T-cell subsets. Overall, our data provide evidence of higher energy demand, impaired metabolic flexibility, and hyperinflammatory responses in aged T cells, and PA reduces metabolic demand in these cells, potentially through increased MD and improved metabolic flexibility.

The m⁶A reader YTHDF2 regulates retinal degeneration caused by aging, which is mediated by its target mRNAs Hspa12a and Islr2.

Summary of key points raised by the Biomarkers of Aging–NIA Symposium 2024.