Aims: Human leukocyte antigen (HLA) polymorphism influences immunity by balancing protection against pathogens with the preservation of self-tolerance. This balance has been proposed to affect longevity, as associations with HLA variants have been identified. However, studies in this field have reported inconsistent findings due to small sample sizes and low-resolution genotyping methods. We aimed to identify HLA alleles linked with longevity by overcoming these previous limitations.

Methods: We performed high-resolution HLA genotyping using targeted sequencing (HLA-seq) in 1,265 long-lived individuals (LLI; ≥94 years) from Germany and compared their HLA allele frequencies to a large control population of 3.4 million individuals from the German Bone Marrow Donor Registry (DKMS) using χ² (chi-square) tests.

Results: Six HLA alleles were significantly associated with longevity. Of those, two exhibited the most robust associations: A*01:01g (OR=0.87; 95% CI: 0.80-0.95; adj. P=0.02) and DRB1*13:02g (OR=1.24; 95% CI: 1.10-1.41; P=0.01). DRB1*13:02g was replicated in the UK Biobank after Bonferroni correction, whereas A*01:01g showed directionally concordant nominal support but did not remain significant after multiple-testing correction.

Conclusions: Both DRB1*13:02g and A*01:01g have previously been implicated in dementia-related phenotypes. These observations support the hypothesis that HLA variation may influence longevity partly through pathways linked to neurodegeneration. This study provides a high-resolution (2-field) HLA data of a longevity cohort, which would be valuable for future investigations.

Hormesis, the biphasic dose-response by which mild stressors trigger adaptive programs that leave cells better defended, has become the standard lens through which geroscience reads lifespan-extending interventions. However, the supporting evidence comes largely from young or middle-aged animals. This review argues that the hormetic window, i.e., the range of stimulus intensities an organism can convert into net benefit, is set not by chronological age but by integrated adaptive reserve, which is shaped jointly by aging biology, cumulative life-history exposures, and comorbidity burden. Because stress-response pathways across NRF2, HSF1, FOXO, AMPK, autophagy, and the telomere-associated DNA damage response are progressively attenuated, and because immune resilience governs the sensing, resolution, and repair phases of any adaptive response, the window both narrows and shifts toward lower doses. Doses clearly restorative in youth can therefore fall on the damaging side of the curve in old age, and two individuals of identical chronological age may respond very differently. We apply this framework to five paradigms: mitohormesis, caloric restriction, thermal stress, exercise, and genotoxic stress, and show that the stimulus generally retains its signal in old age while the downstream amplification machinery becomes rate-limiting. Interventions with explicitly age-dependent effects, including senolytics, NAD⁺ precursors, partial reprogramming, Bcl-xL overexpression, and stem-cell-derived extracellular vesicles, are examined as complementary probes of the same principle. The review closes with implications for geriatric trial design: comprehensive geriatric assessment combined with molecular biomarkers, longitudinal monitoring of a moving window, explicit safety thresholds, and sex-disaggregated analysis.

Cellular senescence is increasingly recognized as a key contributor to many age-related disorders and diseases, and senotherapeutics, therapies that target senescent cells (SCs), have indicated benefits in multiple preclinical models, including models of obesity, metabolic syndrome/diabetes, and their complications. Importantly, SCs are not a uniform population. They differ by originating cell type, stimuli by which senescence was induced, time since induction of senescence, and the tissue and microenvironment in which senescent cells are located, including the composition and magnitude of the senescence-associated secretory phenotype (SASP). Recent studies have indicated that senescent cell populations comprise cells that release inflammatory SASP factors and less inflammatory senescent cells that release growth factors. Senolytics, agents that eliminate senescent cells, preferentially remove the more inflammatory senescent cells while sparing the less inflammatory senescent cells that arise during processes such as acute wound healing. In another study, senescent cell heterogeneity was investigated in adipose tissue impacted by obesity, with a focus on senescence marker expression and cell-type specificity. p16⁺ senescent endothelial cells were a key source of SASP factors within adipose tissue, but p21⁺ senescent preadipocytes and immune cells also contributed substantially to the inflammatory milieu. Identifying and selectively targeting the more pathogenic, pro-inflammatory senescent cell populations may be facilitated by single-cell-level analyses to elucidate the extent of senescent cell heterogeneity and markers of different senescent cell subpopulations. Appreciating the diversity of senescent cells may be critical, since refining senotherapies based on specific SC subtypes may lead to the development of individualized and personalized therapies, potentially improving upon existing broader-spectrum strategies.

We are entering a historic demographic transition: within decades, one-third of our lives will unfold after age 60, and functional decline typically begins ten to twenty years before disease onset. Yet aging is increasingly malleable: today’s 68-year-olds show the functional profile 62-year-olds showed in earlier cohorts, a measured gain in intrinsic capacity. This gain has not yet translated into a matching compression of morbidity, and the gap between lifespan and healthspan continues to widen. Closing it through geroscience-based prevention is both a scientific opportunity and a public health necessity.This Call to Action synthesizes contributions from 60 experts convened at the Paris Healthy Longevity Summit (May 20, 2026, French National Academy of Medicine, Paris) under the High Patronage of President Emmanuel Macron, organized around one guiding question: how to make healthy longevity accessible to the greatest number of people. Contributions were synthesized into five priority pillars and fifteen actions.Five priority pillars emerged: embedding prevention across the life course; large-scale deployment of the WHO’s ICOPE program; adapting health care professional training; investing in geroscience research and biomarker validation; and changing the cultural image of aging while reorganizing care around healthy longevity. Key recommendations include a healthy longevity check-up from age 50, systematizing ICOPE assessment at every point of contact with the population, a geroscience biomarker-validation consortium, and territorial Healthy Aging Coalitions to reduce socioeconomic gaps in healthy life expectancy.It is addressed to public authorities, health care institutions, research funders, employers, insurers, and civil society: the evidence is converging, and stakeholders are ready to act.

Aims: Δ133p53α is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We previously reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes in progeria model mice (heterozygous Lmna^G609G/+). The anti-aging effect of Δ133p53α was attributed in part to reduced levels of the proinflammatory cytokine IL-6. This study aims to comprehensively profile Δ133p53α-induced changes in cytokines and chemokines.

Methods: A Luminex-based multiplex quantitative assay was performed using mouse serum samples from transgenic Δ133p53α-expressing Lmna^G609G/+ mice and non-expressing controls. Quantitative RT-PCR and RNA in situ hybridization assays were used to assess Cxcl10 expression in mouse tissues. In addition, gene expression datasets from human tissues were analyzed.

Results: In the Luminex assay, used as an exploratory screen, transgenic Δ133p53α expression was suggestively associated with reduced serum levels of not only IL-6 but also CXCL1, IL-1α, and CXCL10. We further characterized CXCL10, which has not previously been linked to progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) Δ133p53α-expressing Lmna^G609G/+ mice showed reduced Cxcl10 expression in the liver, spleen, and brain, major organs that produce CXCL10, compared with age-matched non-expressing controls. In naturally aged wild-type mice (2 years old), transgenic Δ133p53α expression also significantly repressed Cxcl10 expression in the spleen and brain. An inverse association between CXCL10 and Δ133p53α levels was observed in human spleen tissues.

Conclusion: CXCL10, a proinflammatory chemokine elevated in both accelerated and natural aging, is a potential target of the anti-inflammatory activity of Δ133p53α.

Aging is a complex biological process, which is affected by several factors, lifestyle, diet, genetic or epigenetic factors, environmental stress, and metabolisms. Among others, several reports observed increased glycolysis in senescent cells (SnCs) and individual aging, whose causal effects or biological mechanisms have been unclear. Recently, we identified phosphoglycerate mutase 1 (PGAM1)-checkpoint kinase 1 (Chk1) binding as a booster for glycolytic metabolism and cell viability in SnCs. Secretory phenotype of inflammatory factors, known as senescence associated secretory phenotype (SASP), is one of prominent properties in SnCs, which accelerates chronic inflammation and aging-relevant dysfunctions in tissues. Inhibition of PGAM1-Chk1 binding removes SnCs and suppresses SASP, alleviating organ damage and pulmonary fibrosis in vivo. Thus, PGAM1-Chk1 interaction represents a target for senolysis to preserve resilience in aging.

Alzheimer’s disease (AD) and related dementias are closely associated with alterations in microglial states. These microglial changes occur in response to amyloid-β (Aβ) accumulation and aberrant tau phosphorylation and can either protect against or exacerbate AD progression, depending on factors such as disease stage, genetic background, and environmental influences. This review focuses on recent advances in understanding the protective functions and features of microglia during the early stages of AD, while highlighting the outstanding questions regarding how these protective states deteriorate and become dysfunctional as the disease progresses. Interestingly, epidemiological studies have suggested an inverse relationship between AD and cancer incidence, and in this context, we provide a comparative analysis of microglial phenotypes in AD and cancer to speculate on how insights from anti-tumor microglia may inspire new strategies for reprogramming microglia to combat AD and related dementias.

Aims: This study aimed to characterise the natural killer (NK; CD3^-CD16⁺CD56⁺) and monocyte compartments in 54 participants by analysing absolute cell counts in relation to age, sex, cytomegalovirus (CMV) serostatus, an established marker of immune ageing, and interleukin-6 (IL-6) values, as an indicator of inflamm-ageing.

Methods: The analysis was conducted in a cohort of Sicilians (28 females and 26 males) aged 19-110 years, including 20 adults (19-64 years), 15 older adults (68-88 years), 11 long-living individuals (93-104 years), and 8 semi- and supercentenarians (105-110 years; hereafter referred to as the oldest centenarians). Multiple negative binomial regression models were used to assess the independent effects of age, sex, CMV serostatus, and IL-6 concentrations on NK and monocyte counts.

Results: Although NK cells and monocytes are generally reported to increase with age, adjustment for covariates revealed that NK cell counts showed only a non-significant age-related trend. In contrast, no statistically significant independent association with age was detected for monocytes. A statistically significant sex effect emerged, with men exhibiting higher NK cell counts than women. Monocyte counts were significantly and positively associated with IL-6 levels.

Conclusion: These findings suggest that previously reported associations of advanced age, particularly extreme longevity, with higher NK-cell and monocyte counts may not be independent of sex, in the case of NK cells, or of chronic low-grade inflammation, as reflected by IL-6 levels, in the case of monocytes. Given the observational design, these results should be interpreted as adjusted associations rather than evidence of mediation or causality.

Over decades, nomenclature in erythrocyte cell death research has been unrefined. Recently, several attempts have been made to adapt the nomenclature suggested by the Nomenclature Committee on Cell Death (NCCD) guidelines to erythrocytes. Within the framework of the standardization of terms used in erythrocyte cell death studies, erythrocyte senescence and eryptosis, a regulated cell death of erythrocytes, have been defined and the formal distinction between both events has been recently established. Differences in their physiological role have been underscored, and markers that can be used to distinguish between erythrocyte senescence and eryptosis have been identified. As a further step, we aim to dissect cellular senescence in nucleated cells and erythrocytes, identifying their hallmarks, key triggers, molecular mechanisms, immunity-related effects, as well as physiological aspects. Available evidence suggests that cellular senescence in nucleated cells can be considered an active biological program, while erythrocyte senescence rather reflects a more passive, gradual accumulation of cellular damage. Fundamental mechanism-based and physiological differences between senescence in nucleated cells and erythrocytes highlighted in this mini-review indicate that the use of the term ‘erythrocyte senescence’ should be discouraged as misleading. Instead, the term ‘erythrocyte aging’ might be more appropriate.

Somatic mutations accumulate in tissues throughout life and are increasingly being recognized as contributors to aging. While their role in cancer has been extensively characterized, their occurrence and functional impact in the cardiovascular system remain poorly understood, partly due to technical limitations in detecting low-frequency and cell-specific variants. Recent advances in single-cell sequencing have begun to unveil how somatic mutations accumulate both in vascular resident cells, including vascular smooth muscle cells, and in circulating hematopoietic cells, such as those associated with clonal hematopoiesis of indeterminate potential. Both resident vascular cells and infiltrating immune cells harboring clonally expanded somatic mutations may influence vascular pathology. This mini-review summarizes the current knowledge on somatic mutation accumulation in the vasculature, focusing on recent studies and the techniques applied for their detection. In addition, we discuss emerging evidence for the functional relevance of somatic mutations in aging and age-related vascular disease.