Longevity Papers

Geroscience - the interdisciplinary field investigating the causal relationship between the biology of aging and age-related chronic disease - has undergone a remarkable evolution since its formalization within the United States National Institutes of Health in the early 2010s. Grounded in the recognition that aging is the paramount modifiable risk factor for most noncommunicable diseases, geroscience has produced a coherent molecular taxonomy of aging processes (twelve hallmarks), delineated pro-aging and anti-aging molecular pathways (gerogenes, gerosuppressors, and gerozymes), and catalyzed a new clinical vocabulary - geroprotection, gerodiagnostics, and gerotherapeutics. Two institutional milestones anchor the field's translational ambitions: the WHO's codification of Ageing-Associated Decline in Intrinsic Capacity as ICD-11 code MG2A; and the FDA's acceptance of the Targeting Aging with Metformin (TAME) trial - the first prospective clinical trial designed to delay aging as a composite multi-disease outcome, currently underway. The biomarker science of aging has advanced in parallel, from first-generation DNA methylation clocks to organ-specific plasma proteomic signatures capable of predicting various age-related diseases with clinical-grade precision. The gerotherapeutic landscape has expanded substantially. Metformin, which engages more aging hallmarks than any other candidate gerotherapeutic, provided the regulatory impetus for TAME; in a rigorous 40-month multi-omics study in cynomolgus monkeys, it decelerated plasma proteomic biological age by 6.41 years - the strongest pharmacological evidence to date for systemic biological age modification in a primate model. Senolytics and senomorphics target senescent cell burden; SGLT-2 inhibitors represent the first approved class with direct senotherapeutic properties; GLP-1 receptor agonists attenuate inflammaging; NAD⁺ precursors restore mitochondrial and sirtuin function; and the gerozyme (15-PGDH) inhibitor offers a mechanistically distinct pro-regenerative approach with emerging relevance as an adjunct to GLP-1 receptor agonist therapy. Multidomain lifestyle programs address multiple aging hallmarks simultaneously and have demonstrated measurable intrinsic capacity improvement in randomized trials. Building on these foundations, this review proposes the Geroscience-Responsive Aging Care Ecosystem (GRACE) - a three-element service model operationalizing geroscience and gerotherapeutic evidence within the WHO Integrated Care for Older People (ICOPE) framework.

As global life expectancy rises, age-related musculoskeletal decline poses a growing public health challenge-impairing mobility, increasing frailty, and diminishing quality of life for billions worldwide. Functional deterioration often begins in midlife, yet effective early interventions remain limited. Metformin, a widely prescribed antidiabetic drug, has shown geroprotective potential. However, its capacity to preserve musculoskeletal health during early aging remains poorly defined. Addressing this gap is critical to developing scalable, cost-effective strategies to extend healthspan. Here, we investigated the effects of midlife metformin treatment in male C57BL/6 J mice by comparing young, untreated middle-aged, and metformin-treated middle-aged groups. Metformin treatment was initiated at 30 weeks of age and continued through 53 weeks. Frailty was evaluated using composite clinical and functional indices, while musculoskeletal health was assessed through motor tests and detailed histological analyses of muscle, bone, and joint tissues. Metformin-treated middle-aged mice maintained body weight comparable to that of young adult controls, preventing excessive age-associated weight gain. Both clinical and performance-based frailty scores were significantly attenuated. Muscle strength, endurance, and mass were preserved, alongside increased muscle fiber size, enhanced capillary density, and reduced fibrotic remodeling. Bone integrity was similarly maintained, evidenced by preserved trabecular architecture, osteoblast abundance, and collagen organization. Additionally, metformin supported locomotor function by preserving gait parameters and knee joint structure, including articular cartilage thickness and chondrocyte integrity. Collectively, these findings demonstrate that metformin administration supports healthspan by attenuating frailty and preserving musculoskeletal integrity in middle-aged mice, reinforcing its potential as a scalable geroprotective intervention targeting early aging.

Aberrant protein acylation by reactive acyl species (RAS), termed carbon stress, is a major driver of aging and metabolic disease. While enzymatic deacylases such as sirtuins counteract aberrant acylation, whether endogenous metabolites can directly neutralize RAS remains unclear. Here, we report that nucleophilic metabolites (taurine, spermidine, and ethanolamine) react with acyl-CoAs, preventing aberrant protein acylation and potentially extending lifespan. We demonstrate that spermidine scavenges acetyl-CoA within the catalytic pocket of p300, a histone acetyltransferase, and extends lifespan in Drosophila. Taurine supplementation in mice fed a high-fat diet promotes N-fatty acyl taurine formation, confirming in vivo scavenging of RAS. These findings identify endogenous nucleophilic metabolites as scavengers that neutralize carbon stress, with implications for combating aging and metabolic disease.

Neuronal aging pace varies markedly between individuals, but what drives this variation remains unknown. Using cell-type-specific transcriptomic clocks applied to single-nucleus RNA sequencing data from 226 adults (ages 20-90), we quantified neuronal aging residuals as a donor- dominant phenotype. Variance decomposition revealed that microglial transcriptional programs predict inter-individual variation in neuronal aging residuals, a directional asymmetry consistent with a non-cell-autonomous relationship between microglial states and neuronal aging trajectories. This asymmetry is accompanied by an age-dependent shift from homeostatic to inflammatory microglial dominance beginning in midlife, with inflammatory dominance probability rising from 26% at age 35 to 92% by age 65, replicated in an independent cohort. IFN{gamma} signaling emerges as the dominant microglial program associated with accelerated neuronal aging in late adulthood. Candidate regulators of microglial IFN{gamma} activity (HIF1A, CEBPB, and EZH2) are computationally prioritized as intervention targets warranting functional validation.

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes and their interactions remain unclear. CXCL13 is a critical chemokine that shapes germinal center organization, but the regulation of human-specific CXCL13+ Tfh cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in T follicular helper (Tfh) cells, the cell type that provides T cell 'help' to B cells in germinal centers (GCs). Tonsil organoids from older donors generated weaker influenza-specific antibody responses, which we traced to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13+ GC-Tfh cells accompanied by accumulation of Tfh precursor states. Trajectory analysis showed that aging arrests Tfh cell maturation at the early activated precursor transition, and CRISPR perturbations identified BACH2 and SOX4 as transcriptional regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.

As the first organ to develop in utero, the human heart undergoes extensive molecular, structural and metabolic remodeling during development and must sustain its function throughout life.

Immunosenescence, the age-associated decline in immune function, is a key feature of human aging. In human lymphoid organs, however, the specific immune cell populations that acquire senescence-associated phenotypes during aging and how they influence the surrounding tissue microenvironment remain poorly understood. A spatially resolved map of these senescence-associated immune states in human lymphoid tissues could help clarify their relationship with aging and their potential contributions to the progressive decline of immune function. Here, we integrated single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs). Single-cell transcriptomics of lymphoid tissues from donors aged 18 to 100 years old identified 34 immune and stromal cell types and revealed age-associated upregulation of senescence signatures in specific populations. Spatial proteomic profiling of 99 LN sections from 51 donors (18-86 years) using high-plex immunofluorescence (~20 million cells) mapped senescence markers (p16, p21, HMGB1, yH2AX) at single-cell resolution, revealing diverse senescent-like cell types ("senotypes") and a stepwise shift from extrafollicular to germinal center (GC) localization with age. Notably, we observed focal clonal-like senescence in GC B cells in older donor LNs. Spatial transcriptomics, epigenomics, and metabolic imaging of selected samples further elucidate the multi-omics signatures and underlying mechanisms of functional impairment, metabolic remodeling, and distinct regulatory programs in senescent-like GC B cells. This study presents a comprehensive spatial atlas of senescence-associated immune states in human lymph nodes, revealing cell-type-specific and spatial heterogeneity that may contribute to immunosenescence and the decline of immune function during aging.

Using 30-second voice recordings from 7,081 adults aged 40-70, we trained gender-specific models to estimate voice-predicted age (Voice Age). Voice Age correlated with chronological age comparably to established omic and physiological aging clocks, while capturing an independent dimension of biological aging. Accelerated vocal aging showed association with higher adiposity, impaired sleep physiology, and cardiometabolic risk markers, supporting voice as a scalable, non-invasive functional aging biomarker.