Abstract: The pursuit of extending human healthspan and lifespan has become a central focus in modern biomedical research. Aging is a complex, multifactorial process influenced by genetics, epigenetics, environmental factors, and stochastic molecular events. Traditional approaches, relying on observational studies or single-omic analyses, have provided limited mechanistic insights into the determinants of longevity. Recent advances in multi-omics, genome editing, and artificial intelligence (AI) now offer a transformative framework for predictive and personalized longevity research. In particular, the integration of AI-driven computational modeling, CRISPR-based genome engineering, and comprehensive multi-omic datasets holds the promise of elucidating key molecular drivers of aging and informing targeted interventions.

Abstract: Microglia are a key brain cell population pivotal for homeostasis, and in brain aging and neurodegeneration they exhibit both adaptive phagocytic and maladaptive proinflammatory responses. To understand this dynamics, I independently analyzed five human datasets, totaling 83,190 microglial nuclei and covering Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and aging, as well as one Macaca fascicularis hippocampal aging dataset with 39,589 nuclei. Homeostatic microglia subpopulations in humans exhibited marked heterogeneity in GRID2 and CCDC26 expression. The expansion of GPNMB/IQGAP2-expressing clusters of phagocytic microglia was found to be the most conservative and reproducible response of microglia across pan-neurodegenerative conditions and aging, and the gene PTPRG from this signature was reproducibly evelated in pseudobulk; notably, the entire GPNMB⁺ signature is highly restricted to perivascular macrophages in macaques. Microglia subpopulations expressing ribosomal genes at high levels, along with FTL/H1, C1QA/B/C, TPT1, PLEKHA7, etc., although sometimes considered pathogenic, tended to be youth/health-enriched, and their coexpression modules were strongly increased in young and healthy samples. I also observed ST18⁺ and NRG3⁺ subpopulations, which reproduced across all human datasets and in monkeys, although their nature is not yet completely understood: some marker genes arise from myelin phagocytosis (e.g., ST18), while others may reflect intrinsic microglial expression (e.g., PCDH9). Gene coexpression network analysis revealed SORL1, MAML3, ELMO1, MEF2A/C, ADAM28, ABCC4, and several other genes as key putative regulators of evolutionarily conserved homeostatic modules, while identifying TANC2, NHSL1, FMN1, ETV6, and particularly DPYD as potential central players in activation-related networks. Transcriptional factor analysis revealed FOXP1 as a positive regulator of activation-related genes (e.g., DPYD and LRRK2), highlighted the role of TCF4/12 in activation (via TMEM163 and LRRK2), showed MITF and POU3F1 as regulators of numerous genes within the GPNMB-IQGAP2 signature, and identified FOXP2, FOXN3, FLI1, and KLF12 as key homeostatic regulators, alongside the well-studied MEF2A/C. Although many of these results are highly preliminary, this may shed light on microglial physiology in health and disease.

Abstract: We recently published that phycocyanin, a phycobiliprotein which accounts for up to 20% of Arthrospira platensis dry weight, has a powerful anti-aging effect, greatly extending the chronological life span (CLS) of yeast cells grown in synthetic-defined medium, both under caloric restriction (CR) conditions (0.2% glucose) or under non-CR conditions (2% glucose). In this study, to explore the molecular mechanisms underlying the effects of phycocyanin, we investigated its impact on key signalling pathways involved in aging. Specifically, we performed CLS experiments using ras2Δ and snf1Δ yeast mutants. The Snf1 pathway is known to promote longevity (anti-aging), whereas the Ras2/PKA pathway accelerates aging (pro-aging). We show that, while in the snf1 mutant the anti-aging effect of phycocyanin was still evident, in the ras2Δ mutant phycocyanin did not appear to exert any anti-aging activity, suggesting that the Ras2/PKA pathway may be essential for mediating the anti-aging effect of phycocyanin. To evaluate the activity of phycocyanin under different nutritional conditions, we performed the CLS experiment in a YPDA rich medium. We show that in this medium phycocyanin accelerated the chronological aging of yeast cells, greatly decreasing the CLS, both when glucose was present at low (0.2%) or at high (2%) concentration. Our data suggest that Saccharomyces cerevisiae could serve as a model not only to investigate the anti-aging properties and targets of phycocyanin, but also its potential side effects, possibly present in higher eukaryotes under certain conditions.

Abstract: Recent advances in large language models (LLMs) have unlocked new possibilities for scientific discovery, yet most remain limited to text summarization or hallucination-prone dialogue. Here, we present LongevityLLM—a function-driven AI agent engineered to execute real, reproducible analyses in structural bioinformatics, comparative genomics, and aging biology. Unlike conventional chatbots, LongevityLLM maps natural language queries to deterministic bioinformatics pipelines, producing structured outputs (FASTA, PDB, XLSX, phylogenetic trees, aging clock reports) while grounding all responses in empirical data. The system retrieves and summarizes scientific information from peer-reviewed literature (via Europe PMC) and biological databases (e.g., UniProt). It integrates five major epigenetic clocks—Horvath, Hannum, PhenoAge, Brunet, and Wyss-Coray—as well as AlphaFold2-based structural mutation impact prediction, cross-species ortholog retrieval with phylogenetic analysis, and curated mammalian life-history traits from the AnAge database and incorporates a time-calibrated mammalian phylogeny and the AROCM (Average Rate of Change in Methylation) metric—a cross-species epigenetic biomarker of aging derived from conserved CpG sites. Built on open-source tools and designed for full auditability, LongevityLLM enables researchers to explore questions such as “How is IFI27 implicated across different aging clock models?” or “What is the structural effect of the IL17A-E100K mutation?” through a single natural language query, without compromising scientific rigor. We release LongevityLLM as an open framework to accelerate hypothesis generation, education, and collaborative geroscience.

Abstract: Aging is not an immutable fate but a malleable biological process driven by interconnected molecular, cellular, and systemic failures. While modern medicine excels at managing acute conditions, it largely fails to address the root cause of most chronic diseases – aging itself. In this review, I synthesize current evidence that aging arises from the interplay of stochastic damage and evolutionarily shaped regulatory programs (exemplified by conserved parameters such as AROCM) and manifests through the hallmarks of aging, including genomic instability, proteostatic collapse, mitochondrial dysfunction, cellular senescence, and inflammaging, ultimately driving chronic disease across organ systems. I argue that defeating aging requires a strategic shift from symptom palliation to restoration of youthful function, achieved through three synergistic pillars: (1) elimination of damage (e.g., senolytics, monoclonal antibodies against pathogenic immune clones or DAMPs), (2) reactivation of endogenous repair mechanisms (e.g., caloric restriction, metformin, GLP-1 agonists, transient OSK expression), and (3) cell, tissue, and organ replacement (e.g., stem cell–derived islets, FOXO3-enhanced MSCs). I highlight evolutionary insights from long-lived species, the centrality of chronic inflammation and fibrosis in age-related disease, and the transformative role of AI: from multi-omic aging clocks to agentic systems for target discovery and personalized longevity medicine. The tools to initiate this paradigm shift are already emerging; what is needed now is scientific rigor, interdisciplinary integration, and a collective commitment to treating aging as the fundamental driver of human morbidity and mortality.

Abstract: Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important path for solving this problem is the search for reliable biomarkers that allow for early and differential diagnosis, especially in view of the similarity between clinical manifestations of different forms of dementia. This study provides an overview of the most relevant signaling molecules for diagnosing cognitive disorders. It presents data on the effectiveness of using comprehensive panels of molecular biomarkers in clinical practice, including β-amyloid, CD34, claudin, DRP1, endothelin-1, NF-kB, PINK1, RAGE, S100, α-synuclein, and tau protein, in patients with Alzheimer's disease (AD) and vascular dementia (VD). The study results demonstrate a high diagnostic relevance of the combined use of signaling molecules as a biomarker panel for screening and differentiating neurodegenerative diseases.

Abstract: Cellular senescence is driven by DNA damage, telomere attrition, and metabolic/mitochondrial stress, culminating in a state of durable proliferative arrest accompanied by a senescence-associated secretory phenotype (SASP) that amplifies inflammation and paracrine remodeling across tissues, thereby accelerating functional decline and age-related pathologies. This review examines the molecular mechanisms and in vivo activities of procyanidin C1 (PCC1), a natural dualmode senotherapeutic. Its dual behavior is characterized by an early or lowdose phase in which PCC1 attenuates selected NFκB–driven SASP components while stabilizing redox and bioenergetic homeostasis; under high senescent burden or tumor-associated stress, elevated doses of PCC1 enable the selective reduction of refractory senescent cells and mitigation of pro-tumorigenic SASP outputs, concomitant with modulation of immune infiltration and metabolic reprogramming. PCC1 further exhibits pronounced anti-inflammatory and anti-tumor potential by reshaping inflammatory and chemotactic gradients within the tumor microenvironment. Reflecting broad multi-organ geroprotective activity, PCC1 can exert antioxidative, mitochondrial-supportive, and anti-fibrotic modulation in cardiovascular/metabolic tissues, skin, liver, kidney, and neural niches. Compared with BCL-2 inhibitors or multi-kinase senolytics, PCC1 shows lower cytotoxicity toward normal proliferating cells and fewer indications of platelet or hematopoietic suppression, with its staged regulatory profile and natural scaffold suggesting a wider therapeutic window. Future priorities include quantifying dose–timing transition thresholds, establishing integrated biomarker panels, and optimizing delivery strategies to define its translational potential in precision, phase-adapted senescence and tumor microenvironment interventions.

Abstract: What is the ultimate goal of biogerontology (the study of the biology of aging)? Ask a biogerontologist and a common answer these days is that it is to extend healthspan rather than lifespan. But is this really a coherent aim for the field? Here we argue that it is not.

Abstract: Research into longevity and aging involves comparing the size of cohorts at certain points on survival curves. However, this analysis is oversimplified because it provides limited information about the sample structure and the distribution of lifespan as a trait within the studied population. Here, we introduce a method for estimating lifespan across the entire data range using distribution analysis. More specifically, we propose dividing the lifespan series into intervals, obtaining the frequencies of phenotypes by lifespan within the sample, followed by distribution analysis using the normality crite-rion. Additionally, to visualize the differences, we propose describing the resulting distributions formally using the normal distribution function and the β-function. We demonstrate that the proposed methodology enables to extract additional information from survival data, providing new insights into the processes that occur in populations in response to genetic interventions and shedding light on their impact on ontogenesis. The proposed approach adds a new layer of information to studies of longevity and aging and expands the toolkit of methods used to analyze survival data.

Abstract: Although dry eye disease (DED) is common with age, the cellular and metabolic changes in the lacrimal gland (LG) that contribute to this condition are not fully un-derstood. Here, we applied fluorescence lifetime imaging microscopy (FLIM) to ex-amine metabolic alterations in LG tissue from aged (20-22 months) female C57BL/6J mice, a model of age-related DED, versus young (~3 months) C57BL/6J mice. Phasor analysis of NAD(P)H fluorescence revealed a shift in aged LG toward more glycolytic metabolism and reduced oxidative phosphorylation. We recently identified a novel subpopulation of F4/80-enriched multinucleated macrophages rich in lipids and lipid metabolizing enzymes in aged female mice. Using FLIM combined with immuno-labeling enabled isolation of the metabolic signature of these macrophages, confirming their increased NADPH oxidase 2 (NOX2) activity, an enzyme which generates reactive oxygen species which are characteristically expressed in M1-type macrophages. In-creased phosphorylation of P47phox, associated with NOX2 activation, was also ob-served in these macrophages, supporting their classification as M1-like cells. FLIM thus provides a valuable tool both to capture metabolic changes in the LG overall, and in defining metabolic features of specific cell populations that may be important in diseases such as DED.

Abstract:

The skin serves as the primary interface between the human body and the external environment, functioning both as a protective barrier and a habitat for a diverse array of microorganisms. The skin's varying conditions—dry, moist, and sebaceous—foster the growth of different microbial communities. While these microorganisms typically exist in a beneficial symbiosis with the host, some bacteria, such as Propionibacterium acnes, can lead to skin disorders like acne. Acne is a chronic inflammatory disease of the pilosebaceous units, predominantly affecting high-density pilosebaceous regions such as the face, back, and neck. This condition not only results in physical scarring but also has significant psychological impacts due to societal appearance standards. This review explores the skin and its microbiome, examining their interactions in detail. Additionally, it delves into the pathogenesis of acne, discussing its underlying mechanisms and potential treatments.

Abstract: Engaging in physical activity is known to prevent falls in older adults, however the relative influence of the intensity, duration and frequency of physical activity is unclear. This study investigated the relationship between fall history and the frequency, duration, and caloric expenditure of both low and moderate/high intensity physical activity. Using the Community Healthy Activities Model Program for Seniors questionnaire, weekly frequency, duration, and estimated caloric expenditure were calculated for both low and moderate/high-intensity physical activity for community-dwelling older adult (fallers (n=18); non-fallers (n=15)). Moderate/high-intensity physical activity regression models were significant for identifying fallers while low-intensity physical activity models were not. Further, the non-faller cohort engaged in significantly greater weekly frequency relative to duration of moderate/high-intensity physical activity than non-fallers. This primary research demonstrates the importance of frequency in addition to the duration of moderate/high-intensity physical activity in decreasing the likelihood of community-dwelling older adults being identified as a faller.

Abstract: The primary drivers of age-related decline remain incompletely understood despite progress in characterizing damage mechanisms. We propose the Conglomerate Theory of Aging, which identifies four key products of damage from multiple reactive species as primary contributors to biological aging: metal bioaccumulation, advanced glycation end products (AGEs), advanced lipoxidation end products (ALEs), and persistent metal‑AGE/ALE hybrid complexes. Acting in concert, these components establish self‑reinforcing cycles that accelerate damage accumulation and functional decline. The theory integrates insights from biochemistry, pathology, and clinical observations, linking these molecular entities to multiple hallmarks of aging, including genomic instability, loss of proteostasis, and chronic inflammation. By reframing aging as the outcome of autocatalytic, mutually amplifying damage pathways, the Conglomerate Theory accommodates both stochastic insults and their systemic consequences. This framework also yields testable predictions for intervention, recommending multipronged therapeutic approaches such as metal chelation, antiglycation, and antilipoxidation therapies applied in combination. Such strategies aim to disrupt synergistic damage loops more effectively than single‑target interventions. The Conglomerate Theory thus provides a unified conceptual model for understanding aging mechanisms and guiding the development of broad‑spectrum interventions to extend lifespan.

Abstract: Obesity in elderly individuals is associated with increased levels of inflammatory biomarkers, indicating a state of chronic low-grade inflammation, which has been recently termed as inflammaging and adipaging. Several studies have demonstrated this relationship: Overweight and obese middle-aged and elderly individuals show elevated levels of inflammatory markers like CXCL-16, IL-6, and adipokines compared to normal-weight counterparts. These markers positively correlate with anthropometric parameters indicating increased cardiovascular risk. C-reactive protein (CRP) and fibrinogen levels increase progressively with higher obesity classes in the general population, including the elderly . For instance, CRP levels nearly double with each increase in weight class compared to normal weight individuals. Additionally, the presence of obesity-related comorbidities like hypertension or diabetes further elevates these inflammatory markers. In conclusion, obesity in the elderly is characterized by elevated levels of various inflammatory biomarkers, reflecting a state of chronic low-grade inflammation. This inflammatory state may contribute to the development of obesity-related comorbidities. The clarification of the complementary or independent role of these biomarkers in aging and obesity could lead to targeted therapeutic interventions in this vulnerable population group.

Abstract:

Aging (senescence) is characterized by development of diverse senescent pathologies and diseases, leading eventually to death. The major diseases of aging, including cardiovascular disease, cancer and chronic obstructive pulmonary disease (COPD), are multifactorial disorders, resulting from complex interactions between multiple etiologies. Here we propose a general account of how different determinants of aging can interact to generate late-life disease. This account, initially drawn from studies of the nematode Caenorhabditis elegans, depicts senescence as the product a two stage process. The first stage involves the diverse causes of disease prior to aging, that cause disruption of normal biological function. These include infection, mechanical injury and mutation (somatic and inherited). Second, etiologies largely confined to aging: deleterious, late-life consequences of evolved wild-type gene action, including antagonistic pleiotropy. Prior to aging, diverse insults lead to accumulation of various forms of injury that is largely contained, preventing progression to pathology. In later life, wild-type gene action causes loss of containment of latent disruptions, which form foci for pathology development. Pathologies discussed here include late-life recrudescence of infection, osteoarthritis, cancer and consequences of late-life deleterious mutations. Such latent injury foci are analogous to seeds which in later life, in the context of programmatic senescent changes, germinate and develop into disease.

Abstract: This study presents an interdisciplinary analysis of the biblical phenomenon of exceptional antediluvian patriarch longevity, subsequent rapid lifespan decline, and the unique case of Job's life extension. Integrating biogerontology, population genetics, and statistical analysis, we demonstrate systematic consistency between biblical chronologies and modern biological principles. Results show synchronized decline in total lifespan, age at sexual maturity, and reproductive period, consistent with a transition from slow to fast life-history strategies in response to postdiluvian environmental changes.

Abstract: Aging is a complex biological process marked by gradual functional decline, reduced cellular resilience, and heightened vulnerability to chronic diseases. Maintaining cell health has become a crucial strategy for extending healthspan and promoting healthy aging. Nutrition at the cellular level plays a vital role in this effort, with bioactive compounds from functional foods increasingly recognized for their ability to influence pathways related to aging. Fruitflow®, a water-soluble tomato extract, contains a variety of bioactive compounds, including polyphenols, nucleosides, and phenolic conjugates, that support cardiovascular, metabolic, and immune health. Preclinical and clinical research demonstrate that Fruitflow® helps reduce platelet hyperactivity, lower blood pressure, and enhance blood vessel function. Moreover, emerging evidence suggests that it offers broader cellular benefits, including reducing oxidative stress, decreasing in-flammation, boosting mitochondrial activity, promoting cellular growth, and supporting a beneficial gut microbiota. These actions align with key aspects of aging, including oxidative imbalance, mitochondrial dysfunction, chronic inflammation, and impaired cellular communication. This review outlines current evidence on the cellular and sys-temic effects of Fruitflow®, explores the molecular mechanisms behind these effects, and assesses its potential as a dietary strategy to enhance cellular health and promote healthy aging.

Abstract: Background: The cardiovascular system of older adults is significantly impacted by ageing, contributing to blood pressure (BP) dysregulation, particularly during postural transitions. This study compared short-term cardiovascular compensatory responses of younger adults (YA) and older adults (OA) during sit-to-stand and lie-to-stand. Methods: Participants underwent two active standing orthostatic stress tests, involving 5 minutes of sitting or 10 minutes of lying, followed by up to 7 minutes of standing. Beat-to-beat cardiovascular parameters were assessed using a Finometer (Finapres Medical Systems). Systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and HR were measured at baseline, immediately on standing, and throughout four specific phases after standing: phase 1 (0-30s), phase 2 (30-60s), phase 3 (60-80s), and phase 4 (300-420s). CO-SVR matching was evaluated to assess BP regulation timing. Results: Compared to YA, OA exhibited higher SBP, DBP, MAP, and SVR but lower HR, CO, and SV at baseline. Immediately on standing, OA experienced a greater drop in SBP, DBP, MAP, and SVR, blunted HR, reduced CO, and higher SV. The short-term compensatory responses were delayed (30-60s), particularly in lie-to-stand, due to a transient CO and SVR mismatch observed in phase 1 and subsequent BP stabilization from phases 2-4. Conclusion: OA exhibited short-term compensatory cardiovascular dysregulation, particularly during the transition from a lying to a standing position.

Abstract: Objectives: The rapid aging of the U.S. population has raised concerns about age-related cognitive decline and Alzheimer’s disease. As of 2024, 18% of Americans are ≥65 years—up from 12.4% in 2004—contributing to a projected 7.2 million cases of Alzheimer’s disease among older adults in 2025. Diet is a key modifiable factor for cognitive decline. Therefore, we aimed to characterize diet quality and nutrient intake and to examine the associations between specific dietary components and cognitive performance in older adults in the American Midwest. Design: The study was designed as a cross-sectional observational study. Setting: Community-based recruitment in Brookings, South Dakota, and surrounding areas Participants: A final analytical sample of 72 community-dwelling adults aged 65 years and older Measurements: Cognitive performance was assessed using subtests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery, evaluating episodic memory (Word List Memory/Recall/Recognition), visuospatial skills (Constructional Praxis), and executive function (Verbal Fluency). A composite cognitive score was calculated from memory and visuospatial subtests. Habitual dietary intake was evaluated using structured 24-hour recalls to calculate nutrient intake and the Healthy Eating Index score, supplemented by the Short HEI questionnaire. Demographics, health history, depressive symptoms (Patient Health Questionnaire-9), and sleep quality (Pittsburgh Sleep Quality Index) were also collected. Results: Participants demonstrated suboptimal diet quality (mean HEI score 54.4 ± 9.4; recommended >80), with only 9.7% meeting fiber recommendations, 11% meeting calcium or vitamin A recommendations, and 1.4% meeting vitamin D requirements. In bivariate comparisons, higher cognitive performance was observed in younger participants (75.5 vs. 79.5 years; p< 0.01) and females (78% vs. 50%; p=0.024). Regression models identified significant positive associations between cognitive scores and intakes of dietary fiber (p=0.007), unsaturated fats (mono- and polyunsaturated; p=0.012–0.033), protein (p=0.018), carotenoids (α-carotene, p=0.001; β-carotene, p=0.026; lutein+zeaxanthin, p=0.016), vitamins A (p=0.044) and E (p=0.034), and minerals including magnesium (p=0.006), potassium (p=0.004), copper (p=0.008), zinc (p=0.024), and calcium (p=0.035). Refined grain intake was inversely associated with cognition (p=0.011). Conclusion: In this population, dietary components like fiber and micronutrients were positively associated with better cognitive function, and the overall nutrient intake shortfalls observed highlight the need for targeted dietary interventions to support healthy brain aging.

Abstract: In the event of a heart attack, many cardiac myocytes are irreversibly lost and cannot be replaced, which can lead to heart failure. Several investigations have proved that the Hippo pathway can be manipulated to benefit cardiac myocyte recovery. The Hippo pathway is a cell-signaling pathway involved in cellular proliferation, stem cell differentiation, control of organ size and apoptosis. The pathway’s main effector is a transcriptional co-factor YAP (Yes-associated protein) whose activation is controlled by different regulators like SAV1 (Salvador Homolog 1), NF2 (Neurofibromin 2) and MOB1 (Mps one binder kinase activator). We investigated using DsiRNAs to manipulate the expression of these regulators in cultured cardiac myocytes for their potential in heart tissue healing and protection.Highly potent Dicer substrate siRNAs (DsiRNAs) were used to silence upstream core regulators of the pathway: MOB1, NF2 and SAV1. The DsiRNAs successfully lowered the level of the corresponding genes and proteins. A combination of NF2 and SAV1 knockdowns is more potent than individual knockdowns. However, MOB1 silencing alone, is a very promising target for heart regeneration, was more efficacious than silencing by either NF2 and or SAV1 individually.