Decoding Human Longevity: Genetic and Molecular Insights from Accelerated to Successful Ageing.

Growing interest in Blue Zone populations and a focus on cardiovascular protection are leading to significant discoveries about human longevity. These regions-Okinawa, Sardinia, the Nicoya Peninsula, Ikaria, and Loma Linda-are characterized by a high prevalence of centenarians and relatively low rates of cardiovascular mortality. Despite cardiovascular disease remaining the leading global cause of morbidity and mortality, its relationship with exceptional longevity remains incompletely understood. Much of the existing literature on Blue Zones is descriptive, with limited integration of cardiovascular epidemiology and the biological mechanisms underlying healthy cardiac aging. This narrative review aims to bridge this gap by examining key cardiovascular features associated with longevity, including vascular aging, myocardial remodeling, and autonomic regulation. In addition, we explore mechanistic pathways derived from centenarian studies, such as reduced inflammation, enhanced metabolic efficiency, and favorable neurohormonal balance, to better understand how these factors collectively shape a distinct cardiovascular aging trajectory. By integrating epidemiological patterns with mechanistic insights, this work seeks to provide a more comprehensive framework for understanding cardiovascular longevity and its potential translation into preventive cardiology.

Abstract This review is based on a systematic search and qualitative synthesis of studies from PubMed, Scopus, Web of Science, and Google Scholar, examining pharmacogenomic, genetic, and epigenetic factors influencing metformin's effects on aging and longevity. Additional references were identified from bibliographies and clinical trial registries. Metformin, a widely used antidiabetic drug, has gained attention in longevity research for its biological effects beyond glycemic control. However, responses to metformin vary considerably, especially in aging populations. This review examines the pharmacogenomic, genetic, and epigenetic factors that shape its efficacy and tolerability, emphasizing their relevance to personalized longevity medicine. We discuss key pharmacogenomic variants in drug transporter genes such as SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC47A1/SLC47A2 (MATE1/2-K), which affect metformin absorption, distribution, and clearance. Additionally, polymorphisms in metabolic regulators like ataxia telangiectasia mutated (ATM), LKB1, PRKAB2, and TCF7L2 modulate downstream signaling pathways, most notably adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) that are central to metformin's anti-aging effects. Beyond genetic influences, metformin may exert epigenetic modifications, such as alterations in DNA methylation, histone acetylation, and non-coding RNA expression. These changes have been reported to impact aging-related pathways such as oxidative stress response, mitochondrial function, inflammation, and autophagy. Notably, metformin has been shown in preclinical and translational studies to downregulate aging-associated microRNAs (such as miR-34a) and modulate epigenetic enzymes and antioxidant responses, thereby supporting cellular homeostasis. Preclinical evidence and select human studies suggest that metformin may influence risk trajectories of age-related conditions (e.g., cardiometabolic disease, cancer, neurodegeneration), although direct effects on human longevity remain unproven. Ongoing trials like Targeting Aging with Metformin (TAME) aim to reposition metformin as a first-in-class therapy targeting the biology of aging itself. However, recent findings from trials like MET-PREVENT underscore the need for precision in patient selection, dose optimization, and biomarker integration. By integrating pharmacogenomic and epigenetic profiling, personalized metformin therapy could become a cornerstone in geroscience. This review supports a personalized approach to optimize metformin's benefits in diverse aging populations and outlines future steps for clinical translation.

In recent years, the study of human health and longevity from the perspective of environmental geochemistry has opened up a new field within environmental science. Tungsten (W) and molybdenum (Mo), both belonging to the same group of elements, are essential trace elements for biological systems and play important roles in human health. However, whether the background levels of W and Mo in a region are statistically associated with human longevity remains a scientific question worthy of investigation. This study employs Origin, SPSS mathematical statistical methods, and Overly spatial analysis techniques to investigate this issue within the research area of Yunnan Province, China. (1) Dynamic correlation evolution: The correlation between ω(W) and the longevity index evolved from non-significant during the Fifth National Census to significantly weak positive correlations in the Sixth and Seventh National Censuses. In contrast, ω(Mo) consistently showed no significant correlation across the three census periods. The ratio ω(W/Mo) shifted from a weak negative correlation to a weak but significant positive correlation. (2) Spatial analysis: Regions with high ω(W) values (66 counties) demonstrated clear longevity advantages. The proportion of counties with longevity above the national average first increased and then slightly decreased over time. These high-ω(W) counties were stably clustered in four major geographical units: the Hengduan Mountains, southwestern Yunnan, southern Yunnan, and central Yunnan. By contrast, The longevity advantages in high ω(Mo) value areas (87 counties/districts) exhibited an "inverted U-shaped" trend, widely distributed across six major fault zones and geomorphic regions, yet sharply contracted in the most recent decade. The results suggest that changes in elemental exposure intensity, potentially driven by anthropogenic activities, may be a key factor influencing regional longevity patterns. Provides a basis for exploring the relationship between trace elements in the regional geochemical environment and human health. However, the specific processes and mechanisms underlying these patterns warrant further investigation.

Biological aging is a complex process associated with declining physiological function and increased risk of aging-related diseases. However, its risk factors and molecular mechanisms remain poorly understood. Here, we performed a comprehensive integrative analysis to identify putative risk factors and molecular phenotypes associated with four epigenetic aging acceleration and human longevity. We first investigated the association between aging-related traits and potential risk factors using genome-wide association study (GWAS) data, identifying cholesterol levels, immune cell traits and insulin-like growth factor-1 (IGF1) as associated with longevity. To investigate the molecular mechanisms, we integrated GWAS summary data for epigenetic aging and longevity with five types of molecular QTL (xQTL) datasets, including gene expression (eQTL), splicing (sQTL), alternative polyadenylation (apaQTL), protein (pQTL), and metabolite QTL (mQTL). We identified 30 genes, 11 splicing events, 5 proteins, 3 alternative polyadenylation events, and 39 metabolites associated with aging-related traits, highlighting key regulatory mechanisms that link genetic variants to epigenetic aging and longevity. Drug-target annotation using DrugBank further prioritized therapeutic candidates, including CASP8, PSRC1 and SORT, as potential intervention targets. These findings provide a comprehensive resource for understanding the molecular architecture of aging and highlight potential novel targets for precision interventions in aging-related diseases.

The Role of Nonsense-mediated mRNA Decay in Aging.

Insulin resistance (IR), commonly associated with obesity, is linked to a range of metabolic and immune-related disorders in the contemporary human population. Nevertheless, it is evolutionary well-conserved, suggesting its potential survival advantages to our ancestors. This review aims to explore the intricate interplay between IR and the immune system as well as its implications for the development of immune-metabolic and allergic diseases in the modern era. From an evolutionary medicine perspective, the longevity of ancient humans relied on energy storage to endure food shortages and effectively activate the immune system against various diseases. Under normal conditions, insulin induces glycogen and triglyceride synthesis in the liver and adipose tissues. However, IR directs more glucose to insulin-independent tissues, such as the immune system, which are critical for survival in adverse conditions. The persistent IR in our current lifestyle promotes low-grade inflammation, accompanied by various metabolic and allergic disorders. Critically, this evolutionary mismatch not only explains disease susceptibility but also informs therapeutic design to target immune-metabolic crosstalk. Moreover, our evolutionary analysis demonstrates that the genomic regions near the PTEN, IL27, and NUPR1 genes could play an important role in this interaction across diverse populations.

The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (> 1400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies. Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile characterized by higher levels of primary and secondary bile acids-most notably chenodeoxycholic acid (CDCA) and lithocholic acid (LCA)-lower levels of biliverdin and bilirubin, and stable levels of selected steroids. Notably, elevated levels of both bile acids and steroids were associated with lower mortality. Several metabolites associated with age and survival were inversely associated with metabolite ratios related to NAD+ production and/or levels (tryptophan/kynurenine, cortisone/cortisol), gut bacterial metabolism (ergothioneine/trimethylamine N-oxide, aspartate/quinolinate), and oxidative stress (methionine/methionine sulfoxide), implicating these pathways in aging and/or longevity. We further developed a metabolomic clock predictive of biological age, with age deviations significantly associated with mortality risk. Key metabolites predictive of biological aging, such as taurine and citrate, were not captured by traditional age analyses, pointing to their potential role as biomarkers for healthy aging. These results highlight metabolic pathways that may be targeted to promote metabolic resilience and healthy aging.

While biomedical advancements have significantly extended human longevity, increased lifespan is frequently decoupled from healthspan, as these additional years are often accompanied by frailty and chronic morbidity. Frailty is characterised by a multisystem decline in physiological reserve and renders individuals disproportionately vulnerable to adverse outcomes - including mortality - when faced with health stressors. Consequently, research into the biological mechanisms linking ageing to the onset of frailty is needed. The zebrafish is increasingly utilised as a model for human aging and frailty due to its high degree of genetic homology. With a short lifespan of approximately 3years, zebrafish show several conserved senescent phenotypes, including cataracts, sarcopenia, spinal curvature, and motor decline. Crucially, as in humans, ageing in zebrafish is not strictly chronological; apparent biological age often diverges from calendar age, with physical condition indicating frailty status more accurately. We propose a frailty index designed to evaluate the divergence between successful ageing and frailty in zebrafish. By utilising easily quantifiable phenotypic markers such as spinal curvature and body mass index, this index provides a score that predicts frailty status as validated against expert assessment. Implementing this standardised metric will facilitate cross-laboratory comparisons and enhance the reproducibility of future zebrafish-based ageing research.

Gut microbiota resilience, the capacity of intestinal microbial communities to resist, adapt, and recover from perturbations has emerged as a critical determinant of human health and longevity. Environmental stressors such as antibiotics, pollutants, poor diet, infections, and psychosocial stress challenge this resilience, often leading to dysbiosis (a sustained disruption of microbial community structure and/or function), impaired metabolism, chronic inflammation, and increased disease susceptibility across the lifespan. While dysbiosis has been extensively studied, the resilience dimension remains underexplored, particularly in the context of cumulative and repeated stress exposures. This narrative review explores microbial resilience, identifying environmental disruptors, and their manifestation at life stages, highlighting its hidden yet crucial role in optimizing lifespan. We critically evaluate the consequences of reduced resilience for chronic disease, frailty, and therapeutic response, while emphasizing the protective roles of diversity, functional redundancy, and host-microbe feedback loops. Translational strategies including dietary modulation, microbial therapeutics, behavioral interventions, and precision tools such as multi-omics and biosensors, are assessed for their potential to strengthen resilience and promote healthy aging. By reframing gut microbiota resilience as both a biological property and a public health target, this work advances a novel perspective: that fostering resilience may mitigate environmental insults, personalize interventions, and extend healthspan.

The EAT-Lancet diet (ELD) and plant-based diets (PBDs) are recommended for their potential health and environmental benefits, but comparative analyses of these dietary patterns in relation to mortality risk remain limited. This study aimed to evaluate the associations of ELD and PBDs with mortality and life expectancy in two nationwide cohorts. Participants from the UK Biobank and the US National Health and Nutrition Examination Survey (NHANES) (2003-2018) were included. Dietary intake was assessed using 24-h dietary recalls. The ELD index (ELD-I), overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI) were calculated and categorized into tertiles. Primary outcomes were all-cause mortality, cause-specific mortality, and life expectancy. After full adjustment, the hazard ratio (HR) for all-cause mortality when comparing the highest versus lowest tertiles was 0.87 (95% CI 0.82-0.92) for ELD-I, 0.88 (0.83-0.93) for PDI, 0.90 (0.85-0.95) for hPDI, and 1.14 (1.02-1.21) for uPDI in the UK Biobank; equivalent HRs in the US NHANES were 0.71 (0.65-0.78), 0.71 (0.64-0.78), 0.83 (0.73-0.94), and 1.44 (1.32-1.57), respectively. In both cohorts, PDI was associated with a lower risk of cardiovascular disease mortality, while ELD-I showed inverse associations with cancer mortality and respiratory disease mortality. At age 45years, participants with higher adherence to the ELD-I and PDI had an average increase in life expectancy of 2.07 to 4.31years and 1.33 to 3.90years, respectively. These findings demonstrated that greater adherence to ELD and overall PBD was associated with a lower risk of all-cause mortality and longer life expectancy across diverse populations, highlighting the significant benefits of these environmentally friendly diets for human longevity.

Autophagy is an evolutionarily preserved intracellular degradation process pivotal in maintaining proteostasis, mitochondrial homeostasis, and metabolic equilibrium, all of which are dysregulated with aging. Aberrant autophagy has been recognized as a hallmark of human aging and age-related diseases, including neurodegeneration, metabolic dysfunction, cardiovascular diseases, and cancer. Bioactive natural compounds derived from plants, foods, and marine organisms have emerged as potent modulators of autophagy, offering a promising strategy to counteract aging and promote healthy lifespan. Mechanistically, these compounds regulate autophagy by modulating key signaling pathways, such as AMPK, PI3K/AKT/mTOR, SIRT1, and FOXO, while also alleviating oxidative stress, inflammation, and mitochondrial dysfunction. Natural compounds like polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids exhibit dual roles by restoring age-related suppressed autophagic flux and inhibiting excessive autophagy-induced cell death. In this review, we provide a comprehensive overview of the molecular mechanisms through which bioactive natural compounds modulate autophagy and impact human aging and longevity. We discuss both experimental and clinical evidence supporting their geroprotective effects, limitations regarding bioavailability and dose-dependent effects, and prospects for the utilization of autophagy-targeting natural products in aging intervention strategies.

IntroductionTAS2R38 is a taste receptor gene located on human chromosome 7 that influences sensitivity to bitter tastes and has been implicated in innate immunity, glucose level, and human longevity. However, its potential association with Alzheimer’s Disease (AD) has not been explored. Identifying such a genetic connection could support developing new drugs or repurposing existing ones for AD treatment.MethodsIn this work, we examined the relationship between allele counts of TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing genetic, clinical, and biomarker data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated the potential molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues across brain regions from the Religious Orders Study/Memory and Aging Project (ROSMAP). We evaluated whether FDA-approved drugs targeting the identified e-gene could reduce dementia risk using 1:1 propensity score-matched groups from longitudinal data in the National Alzheimer’s Coordinating Center (NACC) study, by comparing clinical dementia progression trends between the drug-taking and non-taking groups with linear mixed-effects models.ResultsOur results show that TAS2R38 supertasters were connected to a reduced AD risk with advancing age due to its association with various AD biomarkers (p < 0.001). eQTL analysis linked the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (p < 0.001). Furthermore, elevated MGAM expression correlated with more severe Tau burden (p < 0.05) and implicated in mitochondrial dysfunction in AD subjects. Notably, MGAM is a known drug target for diabetes mellitus. In NACC data, individuals taking MGAM-inhibiting drugs (acarbose and miglitol) showed slower clinical dementia rating progression (p < 0.01) in comparison with the non-taking group.DiscussionThis study is the first to report a genetic association between TAS2R38 and AD biomarkers. Our findings, validated in multiple cohorts/matching groups, suggest MGAM as a novel AD drug target with existing FDA-approved inhibitors and demonstrate the potential of TAS2R38 haplotypes to inform precision drug repurposing strategies for AD, which warrants further in-depth preclinical and clinical studies.

Bile acids are cholesterol derivatives, generated by the coordinated intervention of human and bacterial genes, functioning as endogenous ligands for multiple transcription factors and receptors throughout the body. While only two primary bile acids are generated by the human liver, the intestinal microbiota is the source of hundreds of secondary bile acids and microbially conjugated bile acids. Secondary bile acids regulate immune function throughout the body, promote the conversion of thyroid hormone, and regulate energy expenditure in muscle and adipose tissues, ultimately contributing to the beneficial effects of calorie restriction on human health and longevity. Here, we discuss recent advances in our understanding of secondary bile acids, the intestinal microbiota generating them, and their role in immune disorders.

The publication Human Aging and Longevity presents the most relevant issues in modern gerontology, ranging from theories and mechanisms of aging to the development of age-associated diseases, with translation of theoretical approaches in biogerontology into clinical practice.

To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs-687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs)-in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the Duke-EPESE study. Our predictive model incorporating smRNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated AUCs of 0.92 for 2-year survival in Discovery and 0.87 in external Validation. Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.

This article analyzes the relationship between human height and longevity in the urban town of Zaragoza (and its surrounding rural areas) among 11,441 men born between 1886 and 1908. Attention is devoted to population urban-rural differences (a proxy of the food access facility and population density). Previous studies on this topic have not yielded conclusive results. There is still debate as to whether there is a significant relationship between height and longevity, how long it has existed and whether it affects all types of environmental contexts. We used Cox proportional hazards models tracking life trajectories. The results reflect that in the urban sample each additional centimeter of height is associated with an approximate 1% reduction in mortality hazard (HR per mm ≈ 0.999; 95% CI: 0.998-1.000; HR per cm ≈ 0.99). We interpret these results as evidence of a ‘shortness penalty’ primarily affecting lower-stature individuals in urban environments, particularly among those who died before reaching 65 years of age—likely reflecting early-life conditions and accumulated disadvantage.

Dietary interventions such as caloric restriction and periodic fasting improve metabolic health and extend lifespan in preclinical models, yet individuals differ widely in their physiological responses—variation that remains poorly understood but is critical for safe and effective translation to humans. We applied a 2 days per week intermittent fasting (IF) regimen to 10 inbred strains from the Collaborative Cross (CC), a genetically diverse, reproducible panel ideal for dissecting genetic effects on intervention responses. Using longitudinal phenotyping, we measured hundreds of traits, including lifespan. Our results show that sex and genetic background shape physiological responses to IF across metabolic, hematologic, and immunologic domains. Lifespan effects were also sex specific and varied among strains. These findings demonstrate that IF response is genetically determined in a mammalian model with human relevant physiology. We further compared CC results with a parallel study in Diversity Outbred mice, identifying shared predictors of health and lifespan as well as key differences between inbred and outbred populations. Overall, our work highlights the central role of genetics in shaping dietary intervention outcomes and informs efforts to translate IF benefits to human health and longevity.

IntroductionWhile human longevity has increased significantly over the last 2 centuries, the time spent in good physical and cognitive health has not risen proportionately. The incidence of Alzheimer's disease (AD) increases with age, but parental longevity is often associated with better offspring health and lower AD risk. This study aimed to investigate the relationship between parental longevity and AD.MethodsWe included patients with AD and cognitively healthy subjects (over 75 years), collecting family history data, namely maternal and paternal age at death. We performed a logistic regression to evaluate the association of parental longevity and AD risk and linear regression models for the association with age of onset and CSF biomarkers, adjusting for confounders.ResultsWe analyzed 3069 participants from a Portuguese cohort, including 893 AD patients and 2176 cognitively healthy controls. Maternal longevity was inversely associated with AD risk (OR: 0.989, 95%CI = [0.982, 0.997], P = 0.005). In AD patients, higher maternal age of death was associated with an earlier disease onset (β = -0.081, 95%CI = [-0.148, -0.013], P = 0.019). No associations were found between parental longevity and CSF biomarkers.DiscussionMaternal longevity appears protective against AD risk but is linked to an earlier onset in patients. This may indicate that protective factors for AD could become detrimental once AD is triggered. These findings highlight the complex interplay of genetic, environmental, and potentially epigenetic influences on AD.

The objective of this paper was to review the possibility that the QT interval may be a marker of adult human longevity or life expectancy. Following a literature review, data supporting this possibility was assembled and consists of the following. First, in adults, QT interval increases with increasing age. This is analogous to aging-induced hypertension and diabetes mellitus, both of which are associated with shorter longevity. Second, older persons frequently die suddenly regardless of whether or not they have chronic illnesses for which death is expected. Third, longer QTintervals are associated with increased probability of sudden death. Fourth, patients with two conditions associated with accelerated brain aging, namely dementia and Parkinson's disease, show longer QTcs than age-matched controls. Both of these conditions are associated with sudden cardiac death. Fifth, aging processes may affect the molecular determinants of the QT interval, alter heart composition with increased myocardial fibrosis, or alter the amount of sympathetic and parasympathetic tone, any or all of which can alter myocardial repolarization and the duration of the QTc. Sixth, considering the molecular determinants of the QT interval in the aging heart, which has longer transmembrane action potentials, several factors can account for this change, including changes in late inward Na+ current (INaL), IKr, Ica, Ito, and KATP channels. Transgenic mice overexpressing the Kir6.1 subunit of a KATP channel show a prolonged QT interval and reduced longevity, with animals appearing to die suddenly. Seventh, chronic kidney disease, which is associated with a reduced lifespan, is associated with reduced expression of the anti-aging factor Klotho and Klotho-deficient mice have a prolonged QTc and a reduced lifespan. Taken together, there is a cogent case for factors that increase action potential duration in the aging heart, as recognized by increased QTc, to act in concert with other factors to produce fatal arrhythmias leading to sudden cardiac death and shortened longevity.