Unlike younger populations, older individuals often live with multiple systemic conditions that may influence neurofilament light chain (NfL) levels beyond true neuroaxonal injury, complicating its interpretation as a pure marker of neuronal damage. While prior work has examined determinants of blood NfL, none has specifically addressed its contextualization in the geriatric multimorbid setting. This narrative review critically examines the main non-neurological determinants of circulating NfL in older adults focusing on age, renal function, BMI, glycemic dysregulation, cardiovascular disease, and chronic hypoxia and discussing their clinical implications. Renal dysfunction and BMI appear to act as pharmacokinetic modifiers, altering NfL concentrations through reduced clearance and plasma volume dilution, respectively, without necessarily reflecting increased neuronal injury. In contrast, aging, dysglycemia, cardiovascular disease, and hypoxia may function as biologically active confounders, potentially contributing to neuroaxonal damage through neuronal attrition, microvascular injury, cerebral hypoperfusion, and oxidative stress. This distinction carries clinical implications: pharmacokinetic confounders call for adjusted reference ranges, while biologically active confounders represent true sources of neurological vulnerability warranting independent attention. Blood NfL levels in the geriatric population mirror complex neuro-systemic interactions requiring an integrated interpretive approach. Longitudinal monitoring and elderly-specific multivariate models could improve NfL's reliability as a tool in geriatric neurology.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have emerged as a promising therapeutic option for anti-ageing therapy. However, the ageing microenvironment can induce oxidative stress and senescence in transplanted hUC-MSCs, thereby impairing their capacity to delay immunosenescence. Combining MSC-based therapy with antioxidants may enhance therapeutic efficacy. This study explored whether hUC-MSCs could exert enhanced anti-immunosenescence effects when administered in combination with nicotinamide mononucleotide (NMN). Compared with either treatment alone, the combined administration exerted enhanced anti-ageing efficacy, as evidenced by marked alleviation of thymic and splenic atrophy, attenuation of body weight loss, and significant improvement in motor and cognitive functions in D-galactose-induced ageing mice. In vitro results indicated that combined treatment with hUC-MSCs and NMN alleviated cellular senescence in lymphocytes while simultaneously reducing oxidative stress and senescence in hUC-MSCs. Mechanistically, activation of the Nrf2/HO-1 pathway by NMN mitigated hUC-MSC senescence under stress conditions, thereby preserving their anti-ageing properties. Taken together, our study provides a promising combinatorial approach that sustains stem cell function and amplifies anti-ageing efficacy.

The identification of reliable biomarkers of ageing represents a major challenge in biomedical research, particularly in the context of increasing life expectancy and the growing burden of chronic diseases. Among potential candidates, the ABO blood group system has attracted interest as a stable genetic trait potentially associated with inter-individual variability in ageing-related outcomes. This narrative review critically examines current evidence linking ABO blood groups to age-related diseases and biological mechanisms of ageing. A structured search of major biomedical databases was performed, focusing primarily on studies published in the last five years and complemented by seminal earlier reports. Current findings indicate associations between ABO phenotypes and several chronic conditions, including cardiovascular disease, thrombotic disorders, diabetes, cancer, allergies, and cognitive disorders, which substantially contribute to morbidity and mortality in older adults. However, data are contradictory and dependent on ethnicity, genetic background and environmental factors. Non-O blood groups consistently exhibit a higher risk of thrombotic and cardiovascular events, likely mediated by differences in coagulation factors, endothelial function, and hemostatic balance. ABO-related phenotypic variation may also influence processes implicated in ageing, including vascular dysfunction, chronic low-grade inflammation, immune remodeling, glycosylation pathways, cellular senescence, and host-microbiome interactions. However, evidence supporting a direct relationship between ABO blood groups and longevity remains inconsistent and appears to be population dependent. Overall, current data suggest that ABO blood groups are unlikely to represent independent biomarkers of ageing, but rather modest, context-dependent modifiers of biological pathways contributing to susceptibility to age-related diseases. Further longitudinal and mechanistic studies are needed to clarify their role in healthy and pathological ageing trajectories. SUMMARY: ABO blood group system has been associated with susceptibility to several age-related diseases (ARDs). Non-O blood groups show a higher risk of thrombotic and cardiovascular events. Although some studies also suggest a relationship between ABO phenotype and longevity, findings remain inconsistent and appear to vary across populations. Potential mechanisms linking ABO blood groups to ageing include effects on inflammation, vascular function, immune responses, and host-microbiome interactions. Overall, current evidence indicates that ABO blood group is unlikely to represent an independent biomarker of ageing, but rather a modest and context-dependent factor that can influence aging-related mechanisms and contribute to the ARD development.

Interventions targeting conserved aging pathways can markedly extend lifespan in model organisms, yet their efficacy declines with increasing organismal complexity. While this phenomenon is well documented, the underlying constraints remain poorly defined. Here, we integrate comparative experimental data with mechanistic insights to propose a unifying framework explaining the declining ceiling of lifespan extension. We show that in simple organisms, aging is governed by a limited number of high-leverage pathways, whereas in mammals it emerges from distributed, multi-tissue regulatory systems characterized by redundancy, feedback, and competing physiological constraints. By synthesizing findings from Caenorhabditis elegans, Drosophila melanogaster, and rodent models, we identify key determinants of this transition, including metabolic organization, genetic redundancy, endocrine regulation, microbiome interactions, and pharmacokinetic complexity.

"Omic" aging clocks(ACs) represent an established predictor of biological-age(BA)/all-cause mortality(ACM); however, they are expensive and lack interpretability/explainability. We developed a Blood-Biochemistry Age Clock (BBAC) composed of 11 routine blood biomarkers. The AC functions by transforming the individual's levels of blood biomarkers to years added/subtracted according to "biomarker-ACM risk-profile". The BBAC and PhenoAge were calculated for individuals of the UKB cohort and the results were associated with ACM and disease incidence (eight common chronic diseases) using univariant/multivariate Cox mortality analysis. The BBAC calculation procedure was further optimised. Mortality analysis was likewise performed on NHANES dataset with additional ACs (PCAge/LinAge) serving as predictors. Comparisons between ACs were done using Akaike Information Criterion (AIC). In univariate ACM prediction on UKB cohort BBAC outperformed PhenoAge (AIC - 910749.6 vs. 912914.9). Similarly, BBAC was a better univariate disease incidence predictor(lower AIC). In multivariate ACM prediction PhenoAge exceeded BBAC (AIC - 890855.6 vs. 893294.4). Nevertheless, the optimised version of BBAC was better in predicting ACM in uni (BBAC/PhenoAge AIC - 154165.7/155217.6) as well as in multivariant setting (BBAC/PhenoAge AIC - 151006.9/151031.9). For multivariant disease incidence prediction the results were mixed. On the NHANES cohort BBAC and PhenoAge performed similarly, while PCAge and LinAge achieved the best mortality prediction power. BBAC is an explainable/interpretable AC with good ACM prediction ability.

Leukocyte telomere length (LTL) is a biomarker of cellular ageing, with shorter telomeres linked to increased risk of age-related diseases. Although adverse early-life environments have been associated with shorter LTL in later adulthood, it remains unclear whether such differences are already established by early adulthood and which early-life exposures are most influential. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we analysed LTL in 2014 participants at a mean age of 24.5 years, examining associations with 50 parental, childhood, and adolescent factors assessed predominantly before age 17. In a subset of 893 participants with repeated measurements at ages 17 and 24, we also examined telomere length change across late adolescence. Longer LTL was associated with older parental age at delivery, particularly maternal age, while shorter LTL was associated with maternal passive smoking during pregnancy and greater cumulative trauma exposure during adolescence. Telomere length declined by approximately 1.1% per year between ages 17 and 24, with little evidence that exposures influenced attrition rates. These findings suggest that variation in LTL by early adulthood primarily reflects prenatal and earlier developmental influences, consistent with early biological embedding.

Heat shock transcription factor HSF1 maintains proteome integrity via the induction of heat shock proteins. Here, we provide a comprehensive overview on the structure, function and regulation of HSF1 in multiple organisms. We summarize the aging-associated changes of HSF1 function, the reduced inducibility of the heat shock response, leading to a model of age-related stochastic HSF1 activity decline. Besides, we review basal, non-canonic HSF1 functions through regulating distinct transcriptional outputs which support development, reproduction, tissue proteostasis maintenance, growth- and cancer-related anabolic processes. Based on major observations in the nematode C. elegans demonstrating differential regulation of these outputs, we propose a novel mechanistic framework that draws on the life history-coupled programmed remodeling of its transcriptional function at the onset of reproduction. The HSF1 output selection model accounts for the coexistence of diminished stress inducibility with sustained or increased basal HSF1 activity and explains why broad HSF1 activation may benefit proteotoxic diseases but pose risks in cancer-prone conditions. Experimental approaches leveraging age- and tissue-specific transcriptomic, chromatin, and post-translational analyses are outlined, emphasizing selective restoration of protective HSF1 outputs over indiscriminate activation.

Circulating elastin fragments have emerged as potent mediators of inflammaging and systemic aging, yet a fundamental question persists: which anatomical compartments serve as the primary sources of these fragments during aging? Elastin is a structurally restricted protein distributed unevenly across tissues, predominantly at sites subject to repetitive mechanical loading, such as the aorta and large arteries, the lungs, and the skin. It is speculated that age-driven structural deterioration within these compartments, spanning arteriosclerosis, emphysema, and dermal extracellular matrix (ECM) remodeling, coupled with upregulated elastolytic protease activity (including neutrophil elastase, MMP-2, MMP-9, and MMP-12), sustains a chronic, low-grade release of bioactive elastin fragments into the circulation, thereby fueling inflammaging and systemic aging. Delineating the relative contributions of each source is therefore more than an anatomical exercise; it establishes a mechanistic framework for designing tissue-targeted interventions capable of disrupting the ECM-inflammaging axis. This mini-review examines the principal anatomical sources of circulating elastin fragments and the elastolytic enzymes responsible for their generation.

Circulating sex hormone levels decrease in aging, influencing cerebrovascular health. Estradiol has been shown to support female vascular and brain health, though its effects across the menopausal transition remain unknown. Similarly, the influence of testosterone and other hormones in females is not clear. In males, testosterone is associated with positive health outcomes, but the effects of estradiol and other hormones are undetermined. Here, 187 females were categorized as premenopausal, perimenopausal or postmenopausal and 154 males as younger [< 50 years] or older [50-70 years]. Magnetic resonance imaging quantified cerebral blood flow (CBF), arterial transit time (ATT), relative cerebrovascular reactivity (CVR) and a blood draw for circulating sex hormones. In females, estradiol was associated with lower ATT during perimenopause. Testosterone exhibited a U-shaped relationship with CVR in premenopausal females, yet was linked to lower CBF and CVR, and longer ATT in postmenopausal females. In males, higher testosterone was correlated with greater CBF in younger participants, while higher estradiol and follicle-stimulating hormone were associated with lower CBF in older males. These findings highlight life stage- and sex-specific associations with between hormones and cerebrovascular markers, emphasizing the potential for hormone-targeted, age and stage-specific interventions to support cerebrovascular health.

Animal lifespan depends on coordinated gene expression networks that regulate metabolic adaptation, proteostasis, and stress resilience in response to environmental challenges. Histone variants are key regulators of chromatin dynamics, orchestrating nucleosome remodeling, DNA accessibility, and gene expression. While the role of histone H3.3 in aging and animal survival has been explored across model systems, the contribution of other replication-independent histone variants remains less well-defined. Here, we demonstrate that the evolutionarily conserved histone variant HTZ-1/H2A.Z is essential for organismal survival. In the nematode Caenorhabditis elegans, loss of HTZ-1/H2A.Z disrupts gene expression programs associated with longevity, including those activated in insulin/IGF-1 deficient daf-2 mutants and in mitochondrial Complex I deficient animals. Together, our findings show that HTZ-1/H2A.Z regulates gene expression programs that coordinate metabolic and proteostatic pathways, thereby fine-tuning stress responses and promoting lifespan in animals.

Cardiac calcification is an age-associated pathological process that contributes to cardiac dysfunction, arrhythmia, and sudden cardiac death, yet its underlying mechanisms remain unclear. Cardiac fibroblasts (CFs) have emerged as key mediators of ectopic calcification through osteogenic differentiation. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, has been implicated in cardiovascular pathology beyond its canonical role, but its involvement in cardiac calcification is unknown. In this study, aged mice exhibited cardiac dysfunction, interstitial fibrosis, and myocardial calcium deposition, accompanied by upregulation of osteogenic markers, including Runx2, OCN, and Osx. PCSK9 expression was increased in aged hearts and enriched in DDR2-positive cells. In vitro, senescent CFs displayed enhanced osteogenic differentiation, characterized by increased calcium deposition, alkaline phosphatase activity, and elevated expression of osteogenic markers. Recombinant PCSK9 promoted osteogenic differentiation in young CFs, whereas genetic deletion of PCSK9 attenuated these effects in senescent CFs. Pharmacological experiments suggest that PCSK9-mediated osteogenic differentiation is associated with activation of the ATF4 pathway and upregulation of Runx2 expression. These findings support a role for the PCSK9-ATF4-Runx2 signaling axis in osteogenic differentiation of CFs, providing new insights into age‑related cardiac calcification and identifying this pathway as a hypothesis‑generating candidate for future investigation.

Exceptional longevity has increasingly been recognized as a distinct biological state associated with unique immune and inflammatory profiles. However, the innate immune characteristics associated with extreme aging, particularly following viral infections, remain incompletely understood. Toll-like receptors (TLRs) play central roles in pathogen sensing and inflammatory signaling, including during SARS-CoV-2 infection, yet their relationship with exceptional longevity has not been clearly defined. Here, we quantified TLR gene expression in peripheral blood from unvaccinated older adults who recovered from COVID-19 prior to vaccination (38 nonagenarians and 8 centenarians). Among the receptors analyzed, TLR2 was the only gene differentially expressed, showing lower expression in COVID-19-recovered centenarians compared with recovered nonagenarians. Importantly, this difference was not associated with COVID-19 severity, suggesting that TLR2 expression in this cohort reflects an age- and recovery-associated immune characteristic rather than clinical outcome. Exploratory comparison with centenarians without prior COVID-19 (n = 10) indicated that reduced TLR2 expression was not simply a constitutive hallmark of extreme aging, but may instead reflect a distinct post-infectious innate immune remodeling. Together, these findings identify a distinct TLR2-associated immune signature in centenarians recovered from COVID-19 and suggest that exceptional longevity may be associated with a distinct post-infectious innate immune remodeling following SARS-CoV-2 infection.

We discovered a Sjögren's disease (SjD)-like state in the programmed cell death 1[+] (PD-1[+]) niches of the spleen and submandibular glands of 36-week-old female Nishiura (NI) mice, characterized by the formation of tertiary lymphoid structures (TLS) by senescence-associated (SA) immune cells, production of anti-α-amylase autoantibodies, and reduced saliva secretion. Co-culturing B220[+]/PD-1[+] cells derived from the spleens of NI mice with CD4[+]/PD-1[+]/CD153[+] (SA-Tfh) cells for 48 h enhanced IgG and senescence-associated secretion phenotype production in both cell types. Conversely, transplantation of spleen-derived SA-Tfh cells from NI mice expanded TLS in the submandibular glands of recipient mice. Meanwhile, a retrospective histopathological cohort study of seven SjD patients aged 50-70 revealed that the fibrogenic capacity per SA-Tfh cell significantly increased with age. Collectively, these data suggest that TLS formation associated with SA immune cells in the submandibular glands is a key mechanism in SjD.

Aging is a major driver of hematological impairment and a significant risk factor for hematologic malignancies. CD34[+] hematopoietic stem and progenitor cells (HSPCs) represent a critical cellular compartment in which age-related changes converge to promote leukemogenesis. This review synthesizes contemporary findings on the interplay between intrinsic hallmarks of aging, including genomic instability, telomere attrition, epigenetic drift, and mitochondrial dysfunction, and extrinsic factors, including chronic inflammation and bone marrow niche remodeling, in the reprogramming of CD34[+] cell fate. These alterations promote clonal hematopoiesis of indeterminate potential (CHIP), impair immune competence, and increase susceptibility to malignant transformation. Special attention is directed towards CD34[+]CD38[-] subsets, which possess leukemic stem cell (LSC) functionality and demonstrate resistance to standard treatments. Emerging biomarkers, including CD123, CD96, IL1RAP, and CD133, are discussed in relation to disease progression and therapeutic targeting. We emphasize how aging-related inflammatory signaling and metabolic changes preferentially benefit pre-leukemic clones. Ultimately, we investigate therapeutic approaches designed to disrupt leukemogenesis by focusing on aging mechanisms, the senescent microenvironment, and vulnerabilities specific to leukemic stem cells (LSCs). This review contextualizes CD34[+] cell biology within aging mechanisms, offering a cohesive view on illness onset and highlighting prospects for early intervention in older populations.

Cellular senescence, an irreversible state of cell cycle arrest, has emerged as a critical contributor to tissue dysfunction and organismal aging, and is implicated in a range of pathological conditions including atherosclerosis, tissue fibrosis, neurodegenerative diseases, and cancer. Mounting evidence underscores the central role of the Hippo signaling pathway in regulating fundamental biological processes such as cell proliferation, senescence, and apoptosis in mammals. In its active state, the Hippo pathway facilitates the cytoplasmic sequestration of the transcriptional co-activators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), thereby promoting cellular senescence. Conversely, inhibition of Hippo signaling enables nuclear translocation of YAP/TAZ, which in turn drives the expression of genes associated with cell proliferation and tissue regeneration. Thus, the nucleo-cytoplasmic shuttling of YAP/TAZ serves as a pivotal determinant in the decision between cellular growth and senescence or apoptosis. It is noteworthy that YAP/TAZ deficiency can also trigger senescence through activation of the p16/p53 axis in the nucleus, representing an alternative senescence mechanism. This review provides a comprehensive overview of the canonical YAP-mediated pathways, with a focused discussion on how the Hippo pathway integrates diverse inputs, including oncogenic signals, mechanical cues, circadian rhythms, hypoxic conditions, and chronic inflammatory stimuli, to modulate the molecular and cellular processes underlying senescence.