Aging is multi-causal, yet its molecular hallmarks may converge on a few upstream integrating nodes. We advance the hypothesis that chronic, largely mutation-independent overactivation of the DNA damage response (DDR) is one such node, dysregulating the cell's intact guardian pathways-the tumor-suppressor networks and their negative regulators-to induce senescence, deplete stem-cell pools, and drive inflammaging. Unlike cancer, where mutations inactivate these guardians, aging more often reflects functional dysregulation of wild-type pathways, either chronically overactivated (p53, p16INK4a) or epigenetically silenced (SIRT1, FOXO3, NRF2, Klotho). That the very programs guarding against cancer can, when chronically engaged, come to drive aging we term the guardian paradox. We organize 16 candidate axes-which we term the aging axis-across three evidence tiers, mapped onto the hallmarks of aging, outlining for each a conceptual diagnostic signature and an illustrative restoration strategy, with all numeric biomarker bands and vector details confined to the Supplementary Information as non-clinical placeholders. We set this DDR-integrator hypothesis against mitochondria-, proteostasis-, and reprogramming-first models and pre-specify longitudinal, mediation, and head-to-head tests that could support, demote, or refute it. No integrated human interventional data yet exist; we therefore present a falsifiable research agenda, not a therapeutic protocol.
Src homology region 2-containing phosphatase 1 (SHP-1), encoded by the protein tyrosine phosphatase non-receptor type 6 (PTPN6), regulates immune and metabolic signaling pathways. Although its functions in immune cells and insulin-responsive tissues are separately established, its integrative function in immunometabolic regulation remains unclear. A damaging variant in the PTPN6 gene (Ala455Thr) was discovered in a French-Canadian family and found to be the cause of early-onset emphysema. Using mice carrying this whole-body human-relevant mutation, we studied immunometabolic phenotypes across aging. Old mutant mice showed decreased body, liver and adipose tissue weights, improved glucose tolerance, and enhanced hepatic insulin sensitivity. Despite improved metabolic parameters, aged mutant mice developed liver abnormalities, including increased fibrosis and aberrant immune cell infiltration. Transcriptomic and histological analyses revealed an age-associated accumulation of intrahepatic B lymphocytes and macrophages, accompanied by increased SHP-1 protein levels and activation of Signal transducer and activator of transcription 3 (STAT3) signaling. Experiments in primary hepatocytes and old hepatocyte-specific Ptpn6 knockout mice suggest that these alterations are driven by immune rather than intrinsic hepatocyte mechanisms. These findings identify SHP-1 as a critical modulator of liver immune homeostasis during aging and demonstrate that immune cell infiltration contributes to age-related hepatic remodeling under SHP-1 deficiency.
Understanding the primary molecular and cellular drivers of aging and how they trigger systemic functional decline remains a fundamental challenge. This review focuses on two proposed drivers of aging, cellular senescence and somatic DNA mutations, critically discusses the evidence for their association with organismal aging, and appraises their causal contribution to it. Several studies support the notion that cellular senescence can cause aging, acting through cell-intrinsic and, likely more significantly, cell-extrinsic mechanisms such as the senescence-associated secretory phenotype. Differently, the mutational burden is strongly correlated with aging, but we argue that the causal contribution of altered DNA sequences to age-related functional decline remains difficult to untangle from its originating genotoxic events.
Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear. Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiota was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiota and Indy. Indy down-regulation was linked to reduced expression of Upd3 and Upd2 in the midgut of young flies and Stat92E in old Indy flies, while no change in other members of the JAK/STAT signaling pathway observed. Furthermore, flies double heterozygous for Indy206/+ and upd3Delta/+ alleles lived longer than single heterozygous flies, suggesting synergistic effects on longevity of Indy and upd3 pathways. Altogether, our results suggest that Indy reduction impacts microbiota load and composition, which together with effects of Indy on midgut metabolism contributes to preserved gut homeostasis and extended lifespan.
Trimethylamine N-oxide (TMAO) is a microbiome-based metabolite known to increase with age, cardiovascular and other diseases, with average concentrations mostly higher in males. It was recently found to be associated with neurodegenerative diseases. In this context we aimed to investigate associations between TMAO, cardiometabolic risk factors, cognitive function and brain atrophy in older individuals (67.81 ± 8.86 years of age) with normal neurological status. TMAO was measured by liquid-chromatography tandem mass spectrometry in serum samples from 487 individuals. All participants underwent cognitive testing capturing executive function, motor and memory abilities. In 180 of these individuals, brain MRI was performed to investigate vascular and neurodegenerative changes. In the total cohort higher TMAO concentrations were positively associated with advanced age (p=0.01), BMI (p<0.01), fasting blood sugar (p<0.01), HbA1c (p<0.01) and diabetes (p=0.02). In contrast, we observed negative associations with total cholesterol (p=0.01), LDL (p=0.04) and HDL cholesterol (p=0.04). No significant differences in TMAO concentrations were found between females and males. MRI revealed higher TMAO levels to be associated with lower total grey matter, frontal lobar and hippocampal volume (p=0.01). Summarized, TMAO is associated with higher age, cardiometabolic risk factors and brain atrophy, while there was no difference between the two sexes of this community-dwelling elderly cohort. These findings support that TMAO is mainly a marker of aging processes but also associated with neurodegeneration, even though associations with cognitive functioning were not observed.
Metformin is a biguanide and first line drug for type 2 diabetes (T2D) mellitus that is being recognized as a geroprotective agent capable of influencing important hallmarks of aging. Apart from its primary role in lowering blood glucose levels, metformin has been shown to have several effects at the molecular level. It acts by activating the AMPK, which leads to a cascade of downstream events such as the inhibition of mTOR, increased mitochondrial biogenesis, and autophagy, as well as epigenetic modifications. Current findings also showed its capacity to alter the gut microbiota by increasing short-chain fatty acid producing bacteria, indicating the involvement of other systemic pathways that aid in lowering inflammation, increasing metabolic fitness, and keeping epigenetic stability. The Targeting Ageing with Metformin (TAME), a landmark trial which seeks to evaluate metformin's ability to slow down several age-associated diseases, could lead to a paradigm shift in the clinical approach to aging. This article looks at metformin's various effects on aging and longevity by consolidating findings from cellular, molecular, and organismal levels. It also calls for more studies and trials on metformin and aging.
Mitochondria have emerged as key regulators of breast cancer stem cell (CSC) biology. Mitochondrial metabolic pathways, including oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis, are frequently altered during tumorigenesis, highlighting their role in breast cancer pathogenesis. Since breast CSCs are highly dependent on mitochondrial metabolism, targeting mitochondrial DNA (mtDNA) replication may represent a strategy to impair CSC maintenance. Mitochondrial DNA polymerase-γ (POLG), composed of a catalytic subunit encoded by POLG1 and an accessory subunit encoded by POLG2, is essential for mtDNA replication and repair. In this pilot study, we investigated whether targeting POLG could modulate breast CSC activity. Genetic knockdown of POLG1 and POLG2 in MCF-7 cells resulted in mtDNA depletion, reduced mitochondrial protein expression, impaired energy production, and loss of stemness-related features. To pharmacologically target POLG, we tested Alovudine, a nucleoside reverse transcriptase inhibitor known to act as an off-target POLG inhibitor. In MCF-7 cells, Alovudine reduced clonogenic potential, decreased mitochondrial DNA-encoded protein levels, and lowered oxygen consumption. To further validate these findings, we employed the independent POLG inhibitor Zalcitabine (ddC) in additional breast cancer models. ddC impaired mitochondrial respiration, reduced mammosphere formation, and modulated SOX2 and NANOG expression. Preliminary Kaplan-Meier analyses in a cohort of 458 breast cancer patients showed that high POLG1 expression correlates with worse clinical outcomes, including relapse-free and overall survival. Taken together, these findings suggest that POLG supports mitochondrial function and CSC maintenance, highlighting its potential as a therapeutic target and prognostic biomarker in breast cancer.
Italy currently ranks among the world's oldest nations, with adults aged ≥65 years accounting for 24.1% of the population - the highest proportion in the EU - and a projected median age of 51 years by 2050. While life expectancy at birth reaches 85.4 years for women and 81.4 for men, Healthy Life Years amount to only 69.6 and 68.5, respectively, documenting a substantial lifespan-healthspan divide. The prevalence of multimorbidity and disability exceeds 60% in adults aged ≥75 years; women bear a disproportionate share of this burden, both as patients and as caregivers. Meanwhile, the Italian National Health Service (Servizio Sanitario Nazionale, SSN) remains hospital-centric, regionally fragmented, and predominantly reactive, with prevention accounting for a historically modest share of total expenditure. Against this background, longevity medicine is an emerging, prevention-oriented discipline that aims to extend healthspan - defined here as the portion of life lived in good health, with preserved physical and cognitive function and without significant disability or multimorbidity. It integrates multi-omic biomarkers, digital monitoring, adaptive trial methodology, and life-course risk stratification within a translational framework. Although most constituent tools remain at an exploratory or surrogate stage, and clinical utility has yet to be established, the emphasis on early intervention and precision prevention offers potential to reduce the accumulation of age-related disease and ease long-term pressure on the SSN. This position paper analyzes Italy's demographic and epidemiological trajectory, examines the structural constraints of the SSN, and outlines the scientific foundations of longevity medicine. It advocates for multidisciplinary translational research and identifies five strategic investment priorities: (i) clinically validated biomarkers of biological age; (ii) interoperable digital monitoring platforms; (iii) Bayesian adaptive multimodal trials; (iv) explainable-AI risk stratification tools; and (v) longevity-informed curricula in medical training. These proposals should be regarded as a staged agenda for evaluation; their relevance will depend on whether they deliver measurable gains in patient-relevant outcomes, feasibility, and cost-effectiveness within the SSN.
Eliminating both senescent and cancer cells through pharmacological intervention presents a powerful therapeutic strategy against aging and tumor progression. Navitoclax has emerged as a promising candidate with both senolytic and antitumor activity, but its clinical application remains limited due to dose-dependent thrombocytopenia and tumor-specific resistance. To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells. We demonstrate that DMA effectively ablates different types of senescent and cancer cells in vitro by exacerbating their defects in ATP production. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues.
Aging-related chronic diseases are driven by multiple mechanisms, motivating efforts to develop feasible interventions that can attenuate biological aging. DNA methylation-based epigenetic clocks, particularly measures of the pace of aging such as DunedinPACE, are sensitive to relatively short-term changes in aging processes. However, evidence from randomized controlled trials remains limited. We conducted a randomized controlled trial to test a 12-week multimodal lifestyle intervention comprising exercise and dietary guidance involving daily consumption of yogurt containing Bifidobacterium longum BB536 on DNA methylation-based aging measures in overweight men aged ≥50 years. The intervention group exhibited a significant deceleration in DunedinPACE, corresponding to an estimated 2.2% slower pace of aging, whereas no meaningful change was observed in the control group. Exploratory analyses further identified a significant reduction in DNAmCystatinC, a renal-related GrimAge surrogate marker, while no clock within the biological age remained significant after false discovery rate correction. These findings suggest that a feasible, multimodal lifestyle intervention-including exercise and dietary guidance with daily consumption of yogurt containing Bifidobacterium longum BB536-may be associated with short-term changes in selected DNA methylation-based aging measures. Larger and longer-term studies are warranted to confirm the durability and clinical relevance. This clinical trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000057293).
Sarcopenia, affecting over 60% of individuals above age 80, represents a critical challenge for aging populations worldwide. Despite formal recognition as a disease by the WHO in 2016, therapeutic approaches remain limited to exercise and nutritional interventions, with no approved pharmacological treatments. Current management strategies follow a universal paradigm that assumes similar pathophysiological mechanisms across all patients, yet clinical outcomes demonstrate marked variability that may reflect fundamental sex-specific differences in muscle-aging biology. This review interrogates sexual dimorphism in muscle-aging pathophysiology through the lens of three peptide hormones, i.e., apelin, insulin, and oxytocin, and proposes sex-stratified therapeutic strategies. We analyzed pathophysiological mechanisms underlying sarcopenia, focusing on the complex hormonal regulatory network of apelin, insulin, and oxytocin and its effect on satellite-cell dysfunction, proteostasis, stress, and inflammation. Sarcopenia manifests through fundamentally different pathways in men and women. Women experience precipitous muscle loss during menopause through rapid estrogen decline that disrupts apelin signaling, accelerates insulin resistance, and compromises oxytocin-mediated regeneration. Men demonstrate gradual deterioration paralleling testosterone reduction, with differences among individuals in hormonal dysfunction patterns. Apelin serves as a biomarker primarily in women, while myostatin functions specifically in men. Insulin sensitivity exhibits profound sexual dimorphism, with women maintaining superior muscle glucose metabolism until menopause. Current therapeutic approaches may optimize treatments for one sex while producing suboptimal outcomes for the other. Fewer than 30% of muscle aging studies report sex-disaggregated results, creating critical knowledge gaps. Effective sarcopenia management requires a deeper understanding of peptide-hormone deregulation and development of biologically informed therapeutic strategies that acknowledge distinct disease mechanisms in men and women.
Cellular senescence is a stable form of cell-cycle arrest induced by diverse intrinsic and extrinsic stimuli. While senescence contributes to tumor suppression, wound repair, and placental and embryonic development, the chronic accumulation of senescent cells promotes tissue dysfunction, chronic inflammation, tumorigenesis, and age-related diseases. This review provides a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarizes the molecular mechanisms through which they trigger the senescence program. Although these stimuli differ widely, many converge to core effector pathways, resulting in a stable growth arrest. Understanding the varied stimuli and their underlying mechanisms of senescence induction is crucial for revealing the heterogeneity of senescent cells and developing interventions that modulate senescence during aging and disease.
Classical laminopathic progeroid syndromes link nuclear-envelope defects to accelerated aging, but the specific prognosis for each subtype remains unclear. We conducted a PRISMA-guided systematic review and individual-patient data (IPD) synthesis (PROSPERO CRD420251080312; PubMed/Scopus to 16 July 2025). Genetically confirmed IPD constituted the primary cohort; causes of death were harmonized a priori and survival assessed by Kaplan-Meier with log-rank tests. We included 169 studies and two institutional cases, previously illustrated in the literature but not comprehensively characterized, yielding 158 genetically confirmed IPD (61 deaths, 97 censored). Median survival (years, 95% CI) was: HGPS 16.0 (13.42-19.0; n=60), MAD-B 37.0 (24-44; n=21), RD-LMNA 0.92 (0.096-2.50; n=8), and RD-ZMPSTE24 0.03 (0.014-0.047; n=38); MAD-A had no deaths (n=31). Cause-of-death profiles were subtype-specific: respiratory failure predominated in RD (36/45 deaths), cardiovascular causes in HGPS (6/11), and renal complications in MAD-B (4/5). Findings were robust in sensitivity analyses (including clinical cases, risk-of-bias exclusions, and center-specific checks). In sum, survival and mortality patterns differ markedly across classical laminopathic progeria; genetically confirmed IPD resolved by subtype provides more reliable estimates for clinical counseling and trial design in ultra-rare progeroid disorders.
