Nature Aging

Summary Background People with Type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia. Evidence suggests that thiazolidinediones (TZDs) may be protective for dementia onset including Alzheimer's disease and vascular dementia, compared to other second-line antidiabetic medications (SAMs). However, causality remains uncertain due to methodological limitations. We examined the effect of TZD on the risk of vascular dementia and all-cause dementia in T2DM, compared to other second-line treatments. Methods We emulated a pragmatic randomised trial using UK primary care data, Clinical Practice Research Datalink Aurum, between 2003 and 2023 to estimate the comparative effectiveness of initiating a TZD, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, or sulfonylurea (SU) against incident dementia in T2DM adults on metformin therapy. Patients were followed for up to 5 years from 180 days after their first SAM prescription. We used overlap weighting to adjust for baseline confounding and fitted double robust Cox models to estimate adjusted hazard ratios (aHRs). Findings This study included 124,311 participants (mean age 63 years, 61% males, and 20% whites), of whom 595 developed vascular dementia and 1,678 developed all-cause dementia during follow-up. On top of metformin, 8,669 initiated TZD, 30,216 initiated DPP-4 inhibitors, 55,997 initiated SU and 29,429 initiated SGLT2 inhibitors. TZD were associated with a similar risk of vascular dementia compared with DPP-4 inhibitors (aHR 0.89;95% CI 0.36-2.23) and SU (0.58;0.24-1.42). SGLT2 inhibitors were associated with a lower risk of vascular dementia than TZD (0.29;0.09-0.94), DPP-4 inhibitors (0.25;0.10-0.64), and SU (0.17;0.07-0.40). Most patterns persisted in all-cause dementia: SGLT2 inhibitors vs DPP-4 inhibitors (0.51;0.26-0.99) and SGLT2 inhibitors vs SU (0.35;0.18-0.67), with no difference observed between SGLT2 inhibitors and TZDs. Interpretation Dementia risk was similar for TZDs, DPP-4 inhibitors and SUs but was significantly lower for SGLT2 inhibitors, a finding that warrants further investigation. Considering potential cognitive effects when selecting therapies for T2DM is important in an ageing population.

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.

Reduction in the Indy (Im 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 microbiome 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 microbiome and Indy. Indy down-regulation was linked to reduced expression of the JAK/STAT signaling ligands Upd3 and Upd2 in the midgut of young flies, which likely contributes to preserved intestinal stem cell homeostasis. Altogether, our results suggest that Indy reduction impacts microbiome load and composition, which preserves gut homeostasis and extends lifespan through impacts on JAK/STAT signaling pathway. Significance StatementIndy is a fly homologue of mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a central metabolic regulator involved in health, longevity, and disease. Reduction of fly Indy gene activity preserves metabolic and intestinal stem cell homeostasis and extends longevity. Gut microbiota impacts host metabolism, health, and aging. Here we show that Indy reduction prevents age-associated increases in bacterial load and expression of the JAK/STAT signaling ligands Upd3, and Upd2, while maintaining microbiome diversity. These changes likely slow activation of epithelial cell turnover in the gut and contribute to downstream lifespan effects. As the role of INDY and microbiome are conserved across organisms, our study provides a framework to study underlying mechanisms of the effects of reduced Indy and the microbiome on health and longevity.

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.

1Manual frailty index (FI) assessment in mice is a strong predictor of morbidity and mortality, and is frequently used in mechanistic and translational geroscience. However, it is labor-intensive, requires expert training, and is vulnerable to scorer variability. We previously developed a visual frailty index (vFI) that objectively predicts age and frailty using expert-defined, supervised behavioral features extracted from open-field videos. However, relying solely on human-defined features may miss subtle, latent behavioral signatures of aging. Here, we test whether unsupervised behavioral discovery using Keypoint-MoSeq (KPMS) could uncover these hidden signatures and improve the prediction of aging-related outcomes. Using a large dataset of isogenic C57BL/6J (B6J) and genetically diverse Diversity Outbred (DO) mice, we find that unsupervised features are highly predictive of chronological age, biological frailty, and the proportion of life lived. Notably, while supervised features overall outperformed unsupervised features in these tasks, combining both feature sets yielded the highest predictive accuracy across all outcomes. Despite these improvements, models trained on either feature set failed to generalize across strains, confirming that behavioral manifestations of aging are strongly population-specific. These findings demonstrate that supervised and unsupervised machine vision provide complementary information, establishing a highly sensitive, scalable, and non-invasive framework for objective and scalable geroscience in rodents.

Quantitative measures for tracking functional health have generally been lacking. Intrinsic capacity (IC) has been proposed as an appropriate measure, but its metrics have been derived in small datasets and sparse longitudinal data. Using harmonized measures of cognition, locomotion, sensory function, vitality, and psychological well-being from 501,615 UK Biobank participants and followed for a median of 15.5 years, we derived domain-specific and composite IC scores. We examined associations with incident disease, cause-specific mortality, multimorbidity, lifestyle and socioeconomic factors, and multi-omic profiles from Olink proteomics, NMR metabolomics, clinical biochemistry, and blood-cell traits. We found that composite IC declined non-linearly with age, and within-person decline was steeper than the cross-sectional age measures. Participants with greater baseline morbidity, those who subsequently developed incident disease, and those who died earlier in follow-up showed lower IC trajectories across adulthood. The IC domains were only modestly correlated with one another, supporting multidimensionality, yet higher overall IC was associated with lower risk of most diseases examined. The dominant IC domain varied by endpoint, with cognition informative for dementia, sensory function for hearing loss, psychological capacity for depression, locomotion for osteoarthritis, and vitality for cardiometabolic outcomes. IC was also associated cross-sectionally with physical activity, insomnia, smoking, medication burden, and socioeconomic disadvantage. More proteins were found predictive for vitality, and enrichment converged on immune/inflammatory and metabolic pathways. Blood-based surrogates recapitulated part of the phenotypic signal, particularly for vitality. Overall, this IC framework captures longitudinal health trajectories and broad disease vulnerability in a large middle- to older-aged cohort and supports IC as a clinically meaningful, multidomain phenotype of aging and identifies blood-based correlates that may facilitate at-scale future monitoring of aging-related function declines.

Aging causes a progressive loss of tissue homeostasis, with stem cell exhaustion as a major hallmark. Age-associated decline in organ function is widely perceived as emanating from progressive accumulation of cellular damage in adult tissues. However, whether aging trajectories are established early on during development remains an open question. Here, we demonstrate that genetic modulation of cellular aging pathways in larval adult midgut progenitors (AMPs), which serve as the precursors of adult intestinal stem cells and differentiated epithelial cells, dictates the long-term trajectory of intestinal aging in Drosophila. Accelerated cellular aging by genetic perturbation employing Toll or Imd pathway overactivation or elevation of reactive oxygen species (ROS) using ND42 (mitochondrial complex I) knockdown in the AMPs results in aberrant progenitor proliferation, skewed lineage allocation, epithelial barrier dysfunction, and genomic instability. These alterations are accompanied by marked destabilization of AMP islet architecture and widespread changes in age-related molecular signatures, as revealed by bulk transcriptomic analysis. In contrast, decelerated cellular aging mediated by Foxo or Atg8a overexpression results in a decrease in enteroendocrine population and the intestinal barrier remained unaffected. Intriguingly, early-life activation of immune and oxidative stress signaling manifested later in the adult gut as elevated enteroendocrine differentiation, highlighting lasting effects on intestinal regenerative capacity and lineage balance. Together, our findings demonstrate that cellular aging is tightly regulated early on in development and its perturbation can cause developmental disruption hampering adult gut homeostasis, establishing AMPs as key developmental determinants that regulate the trajectory of intestinal aging in Drosophila.

The aging clock paradigm has yielded dozens of specialist models that can estimate chronological age or mortality from virtually any biodata type. Yet each such model operates within a fixed modality, relies on a predetermined feature set, and produces limited biological interpretation. Here, we report Longevity-LLM v0.1, a Qwen3-14B model fine-tuned through supervised and reinforcement learning regimes on DNA methylation, proteomics, clinical biomarker, and RNA expression data. Longevity-LLM achieves high ranks in the recently announced Longevity Bench, including such tasks as cancer survival and RNA- or proteome-based age prediction. After reinforcement fine-tuning, the model achieved a 4.34-year MAE in epigenetic age prediction, surpassing the Horvath multi-tissue clock. In addition to age prediction, Longevity-LLM can carry out numerous other tasks, including proteomic profile generation, for which it significantly outperforms all frontier LLMs. These results demonstrate that a single modestly sized LLM can match or replace purpose-built aging clocks across data modalities. This work constitutes an interim report from the initial sprint of our Multi-Modal AI Gym for Science (MMAI), an initiative dedicated to building foundation models for drug discovery and aging research.

BackgroundGenome-wide studies in late-onset Alzheimers disease (LOAD) have uncovered many risk loci, yet identifying the causal genes and clarifying how these genetic signals connect to molecular and cellular mechanisms relevant to AD pathogenesis in vivo remains challenging. MethodsUsing Caenorhabditis elegans as a model to identify LOAD-associated genes that drive neurodegenerative processes, we focused on 14 understudied genes and their homologs: ABI3/abi-1, B4GALT3/bre-4, CCDC6/T09B9.4, CLPTM1 (two homologs C36B7.6 and R166.2), CNN2/cpn-2, DMWD/wdr-20, ECHDC3/ech-2, MADD/aex-3, NCK2/nck-1, RABEP1/rabn-5, RIN3/rin-1, SLC39A13/zipt-13, TRAM1/tram-1, and USP6NL/tbc-17. We knocked down these genes by RNAi and quantified lifespan, aging-associated degeneration of two neuron classes, PVD and PLM, and associative learning and short-term memory. ResultsLifespan was unaffected by most knockdowns, and only nck-1 and tbc-17 shortened lifespan. Across neuronal assays, multiple homologs modulated aging with clear neuron-class selectivity. Knockdown of aex-3, C36B7.6, cpn-2, ech-2, rabn-5, rin-1, T09B9.4, and zipt-13 attenuated late-life PVD degeneration, whereas R166.2 and tram-1 accelerated early PVD aging. Only two genes affected PLM aging: R166.2 knockdown exacerbated degeneration, while tbc-17 knockdown attenuated it despite its lifespan-shortening effect. In PLM neurons, tbc-17 knockdown, targeting a Rab GTPase-activating protein, also preserved mitochondrial architecture during early aging and shifted heat stress-induced mitochondrial remodeling toward a pattern consistent with improved quality control. In behavioral assays, ech-2 knockdown, targeting an enoyl-CoA-hydratase, enhanced short-term memory during early stages of aging. To further assess how LOAD-linked genes interact with A{beta}-driven neurodegeneration, we developed a model that combines the PVD aging assay with a background expressing human A{beta}1-42 panneuronally. In this model, A{beta} expression accelerated age-dependent PVD degeneration, whereas ech-2 knockdown abolished this A{beta}-induced effect. ConclusionsOur findings show that conserved homologs of several understudied LOAD risk genes causally modulate neuronal aging in vivo in a neuron-class-selective manner, often dissociable from organismal longevity. This C. elegans framework translates human genetic associations into quantitative, aging-linked neuronal phenotypes, and our results further emphasize early endosomal and lipid-related processes as key pathways that warrant functional testing in neuronal aging. This study also provides a tractable platform to prioritize targets for cross-species validation and to test synergy with established LOAD risk genes.

Foundational AI models have recently shown promise for predicting the impact of perturbations on cell states. However, current models typically consider only one cell state at a time, limiting their ability to learn how cellular responses unfold over time, particularly across long trajectories such as diseases of aging. Here, we develop a temporal AI model, MaxToki, trained on nearly 1 trillion gene tokens including cell state trajectories across the human lifespan to generate cell states across long timelapses of human aging. MaxToki generalized to unseen trajectories through in-context learning and predicted novel age-modulating targets that were experimentally verified to influence age-related gene programs and functional decline in vivo. MaxToki represents a promising strategy for temporal modeling to accelerate the discovery of interventions for programming therapeutic cellular trajectories.

Aging is the leading risk factor for cognitive impairment and neurodegeneration, yet molecular changes that unfold in the brain over time, and how they drive this vulnerability, remain unclear. The naturally short-lived African turquoise killifish (Nothobranchius furzeri) offers a powerful model to understand brain aging on an accelerated timescale and test the impact of potential interventions. Here, we present a multi-omic atlas of brain aging of female and male African turquoise killifish from 2 independent genetic strains of different captive lifespans, encompassing single-nuclei RNA-seq, single nuclei ATAC-seq, and bulk ATAC-seq to capture transcriptional and regulatory changes. Interestingly, our atlas indicates that aging leads to a significant expansion of microglia numbers, regardless of sex or strain, which we independently validate using in-situ hybridization. In addition, we identify robust and conserved gene regulation changes, that are consistent with activation of glucocorticoid signalling as a hallmark (and potential driver) of vertebrate brain aging. Furthermore, pharmacological inhibition of glucocorticoid receptor activity starting at middle-age led to significant rescue of key molecular and cellular aging phenotypes. Thus, our study provides a powerful resource and framework to leverage the African turquoise killifish and rapidly uncover actionable pathways driving brain aging.

In C. elegans, prolonged food deprivation during early larval development results in aging-like phenotypes that can be fully reversed upon refeeding, but it remains unknown whether and how this ability persists into later life stages. Here we subjected C. elegans of the last larval stage to starvation, driving them into adult reproductive diapause (ARD). During starvation, ARD worms exhibited a wide spectrum of aging-like phenotypes, including transcriptomic reprogramming accompanying cellular and functional declines. These phenotypes are largely restored within one day of refeeding, suggesting a rejuvenation effect. Time-series transcriptomics, proteomics, and follow-up analyses of the refeeding/rejuvenation process uncovered an intricate coordination between: (1) activation of the IRE-1 branch of UPRER (unfolded protein response of endoplasmic reticulum) to induce chaperone expression; (2) quiescence of the PEK-1 branch of UPRER to avoid translation suppression; (3) up-regulation of the translation machinery to boost protein synthesis. IRE-1, together with its downstream effector, XBP-1, play an essential role in boosting protein synthesis, which is required for complete rejuvenation from the ARD state. These findings indicate that coordination between a high protein synthesis activity and a high protein folding capacity is key to refeeding-associated rejuvenation. HighlightsO_LIRefeeding rapidly reverses aging-like phenotypes in adult reproductive diapause C_LIO_LIRefeeding selectively activates the IRE-1 branch of UPRER C_LIO_LIRefeeding restores protein synthesis in an IRE-1 dependent manner C_LIO_LIRejuvenation requires enhanced translation activity and protein folding capacity C_LI

Dementia incidence has been declining in Western societies for decades, but whether this reflects higher cognitive capacity entering old age, slower cognitive decline, or both remains unresolved. Analysing ~783,000 episodic memory assessments from ~219,000 individuals across five longitudinal cohorts, we find that later-born cohorts benefit from a double dividend: higher memory levels entering old age and slower rates of decline. The projected 20-year cohort advantage at age 80 is of sufficient magnitude to plausibly account for the observed 13% per-decade decline in dementia incidence reported in meta-analyses. Generational gains are disproportionately concentrated among the fastest-declining individuals, and are reflected in lower hippocampal atrophy rates in an independent sample. A formal bounding analysis shows that the double dividend is robust across a range of plausible period assumptions, consistent with environmental conditions operating across the lifespan having reshaped the architecture of human cognitive aging.

A widespread view of neurodegenerative disorders, including Alzheimers Disease (AD), frames their effects as accelerated aging, with the brain-age gap (BAG, the deviation of predicted brain age from chronological age) as a staple biomarker. However, BAG relies on a fundamental, untested assumption: that AD can be identified via age-invariant brain phenotypes. Using invariant representation learning on brain MRI from 44,178 individuals, we created neural representations that optimally convey age information (age-aware) or conversely remove it (age-invariant) while minimizing reconstruction distortion. We provide the first causal evidence that age information is necessary in brain biomarkers for AD detection: age-aware representations achieve competitive state-of-the-art performance and significantly outperform age-invariant ones (0.84 vs. 0.77 AUC, p < 0.001, with external validation). This necessity reveals a conceptual flaw in BAG: by subtracting chronological age, it discards the very information essential for accurate detection. Using conditional decoders to simulate aging trajectories, we found that healthy aging and AD operate along multiple independent anatomical dimensions (deep gray matter, frontoparietal, temporal). AD patients diverge from rather than accelerate healthy aging, showing pathological temporal shifts alongside, remarkably, relative frontoparietal preservation. Furthermore, representational similarity analysis suggests that even models pretrained on non-age tasks (e.g., sex or BMI) implicitly converge toward age-related features when optimized for AD. Given that the AD phenotype cannot be decoupled from age, our results establish a hard limit for age-independent biomarkers and favor multidimensional models that preserve aging structure over unidimensional summaries like BAG.

The spleen contains diverse macrophage subsets that remove aged erythrocytes, prevent the dissemination of circulating pathogens, and shape the adaptive immune response1-3. The mouse spleen hosts red pulp macrophages (RPM), marginal zone macrophages (MZM), marginal zone metallophilic macrophages (MMM), and tingible body macrophages (TBM). However, their transcriptomic identity, ontogeny, and dynamics during aging are unknown. Furthermore, it is not known whether homologous populations of macrophages exist in the human spleen. We find that in mice, MZM and MMM are tissue-resident macrophages that maintain their population via local proliferation, while TBM are slowly replaced by circulating monocytes. Lineage tracing shows that MMM maintain the MZM pool, and that after MMM depletion, circulating monocytes restore MMM. We show that a decrease in MMM abundance in aging precedes changes in other cellular populations and splenic niches. In human spleen, we identify TBM and perifollicular zone macrophages (PFZM) as a single macrophage population homologous to MMM and MZM in mice. We show that in both mouse and human TBM become more abundant during aging. Our results suggest age-related changes in the splenic microenvironment drive changes in tissue-resident splenic macrophage populations with potential importance for the loss of immunologic function in older individuals.

Glucose is the brains primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimers disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival--even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimers disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimers.

The lungs are highly susceptible to chronic disease in advanced age, likely due to the uniquely compromised repair function of alveolar type II (AT2) cells, facultative progenitor cells that maintain the gas exchange surface. Using aging mouse models, single-cell sequencing, and ex vivo organoid assays, we found that homeostatic aged AT2 cells exhibited an Interferon {gamma} (IFN{gamma}) response associated with IFN{gamma}+ CD8+ T cells in tertiary lymphoid structures (TLS). Aged AT2 cells exhibit impaired regeneration in organoid assays and lost markers of an IFN{gamma} response outside the lung microenvironment, demonstrating that elevated local IFN{gamma} influences the state of AT2 cells. Neutralization of IFN{gamma} signaling and immunoproteasome knockout mice with attenuated IFN{gamma} levels partially rescued aged AT2 cell regeneration. Our findings demonstrate that local IFN{gamma} signaling in aging lungs actively represses alveolar regeneration, establishing chronic inflammatory signaling as a cause of age-related decline in the lung. Halting chronic inflammatory processes restored alveolar regeneration and may provide a means to improve lung health in old age.

Alzheimers disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-{kappa}1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-{kappa}1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.

Although lifespan has long been the focus of ageing research, preventing functional decline late in life is a more pressing societal need. Here, we investigate the basis of senescence and declining fitness during replicative ageing in budding yeast, and describe a metabolic perturbation that preserves late-life fitness even on an unrestricted glucose diet. We show that senescence can be prevented by constitutive activation of AMPK, though only for approximately half the ageing population, and use genetic and functional assays to link this heterogeneous response with differences in cytosolic acetyl coenzyme A (Acetyl-CoA) metabolism. In one class of ageing cell, AMPK activity maintains fitness late-in-life through pathways that transport cytosolic Acetyl-CoA into mitochondria, but AMPK also inhibits fatty acid synthesis which leads to lipid starvation in the other class of ageing cell. Therefore, AMPK activity has both positive and negative effects, but we show that constitutive AMPK activity uncoupled from fatty acid synthesis inhibition (the A2A mutant) suppresses senescence and maintains fitness in both classes of ageing cell. We further implicate lipid starvation and excess acetyl coenzyme A availability as major drivers of senescence in replicatively aged wild-type yeast. Our work shows that ageing is not intrinsically associated with declining fitness, at least in yeast, and that re-engineering highly conserved metabolic pathways allows fitness to be preserved very late in life.

Declines in nicotinamide adenine dinucleotide (NAD+) are linked to mitochondrial dysfunction, genomic instability, and metabolic stress that accompany aging and associated processes. While precursor-based approaches elevate systemic NAD, their clinical translation can be constrained by biosynthetic bottlenecks and first-pass metabolism. RENEWAL-NAD+ (ClinicalTrials.gov NCT07336836; retrospectively registered 01/04/2026) was a double-blind, randomized, placebo-controlled Phase 0/1b trial in healthy adults aged 45-75 years (60 randomized; primary analysis n=50) evaluating 5 days of oral LathMized NAD+ (LNAD+), a proprietary physiochemically modulated formulation designed to alter the supramolecular organization and solution behavior of NAD+ while preserving its native molecular structure. The primary endpoints were change in intracellular NAD (icNAD), measured in whole blood, and circulating NAD (cirNAD), measured in separated plasma, relative to baseline. At Day 6, icNAD increased by 53% versus placebo (p=5.48e-14; Hedges g=3.66), while cirNAD was unchanged (p=0.60), demonstrating compartment-selective intracellular NAD+ delivery. Plasma NAD catabolites increased substantially (1-methyl-nicotinamide, MeNAM p=5.39e-13; N1-methyl-2-pyridone-5-carboxamide, 2PY p=2.95e-16), consistent with engagement of downstream NAD metabolic flux. Exploratory analyses identified non-overlapping correlates for the two compartments (cirNAD tracking inflammatory and metabolic markers, icNAD tracking red blood cell indices and NAM). Treatment was very well tolerated: symptom incidence was comparable between groups (p=0.68), only one mild adverse event (nausea, Grade 1) occurred in the LNAD+ arm, and no secondary clinical laboratory, vital sign, wellbeing, or wearable-derived endpoint survived multiplicity correction. These data demonstrate rapid intracellular NAD augmentation after oral LNAD+ dosing with pharmacodynamic evidence of downstream metabolism, compartment-specific physiological signatures, and a favorable short-term safety profile.