npj Aging

Cellular senescence plays a critical role in chronological aging and is implicated in the onset and progression of multiple age-related disorders. Targeting senescent cells represents a promising strategy to reduce disease burden and improve healthspan. Here we report the senotherapeutic properties of salvianolic acid (SA) family members, specifically A (SAA), B (SAB) and E (SAE). From a natural medicinal agent library, we identified selective cytotoxicity of these SA compounds against senescent cells across diverse senescence types and cell lineages. Mechanistically, SAA, SAB and SAE enhance ROS production and target glutathione S-transferase Pi1 (GSTP1), a redox homeostasis modulator, inducing both apoptosis and ferroptosis in senescent cells. Incorporation of SAs into chemotherapeutic regimens enhanced anticancer efficacy and prolonged post-treatment survival. Intermittent SA administration improved physical function and increased healthspan and lifespan in aged mice. Collectively, our study establishes SAs as an emerging class of natural senolytics (phenolic acids) with the capacity to delay aging and alleviate age-related pathologies in advanced life.

Cognitive decline, particularly Alzheimers disease, represents a significant global health concern. While traditional risk factors are well documented, an evolutionary perspective grounded in life history theory offers critical insights into the intergenerational dynamics influencing cognitive aging. This study empirically analyzed the relationship between reproductive history and late-life cognitive performance in women, as measured by the Montreal Cognitive Assessment Colombian version (MOCA-Col). Specifically, we examined the moderating role of the number of grandchildren on the association between parity and cognitive performance. Using an observational, cross-sectional design with a sample of 145 women (mean age = 69.9 years), a cumulative ordinal logistic regression model was fitted to MOCA-Col scores, incorporating age and the interaction between the standardized number of children and grandchildren. A higher number of children was significantly associated with lower odds of being in a better cognitive category ({beta} = -0.869, SE = 0.305, p = 0.0104, OR = 0.42). Crucially, a significant positive interaction between number of children and number of grandchildren was observed ({beta} = 0.354, SE = 0.093, p < 0.001, OR = 1.42), indicating that the negative association between parity and cognition progressively attenuated as the number of grandchildren increased. This evidence supports human life history models and the grandmother hypothesis, suggesting that intergenerational investment may mitigate the cumulative biological costs of reproduction. The findings reflect an evolutionary trade-off between early reproductive effort and later somatic maintenance.

Aging is one of the primary drivers for the decline of female fertility, and oocyte quality is the main cause for ovary aging, which is related with infertility. Although some effective anti-aging natural components have been reported, highly efficient strategies for reversing ovary aging remain lacking. In this study, we reported that peptide elamipretide reserved ovary function for female fertility during maternal aging. Our findings demonstrated that elamipretide improved aged human oocyte maturation and fertilization. Elamipretide injection increased the litter size of aged mice, and improved oocyte quality with the reverse of follicle and embryo development defect. Metabolomic and transcriptomic analyses demonstrated that multiple biological processes in oocytes were significantly reserved. Both nuclear maturation and cytoplasmic maturation of aged oocytes were improved, showing with enhancing cytoskeletal dynamics, mitochondrial metabolism and organelle rearrangement. In vitro supplementation during culture also restored oocyte developmental competence in both mouse and porcine oocytes. Mechanistic analysis suggested that elamipretide reversed age-related ovarian damage via synergistic activation of the Vitamin B6-VEGF axis. Therefore, our study proposed a new peptide therapy for aging-induced infertility, showing that elamipretide reverses aged oocyte quality for fertility by promoting both nuclear and cytoplasmic maturation through the coordination with VEGF signaling pathway.

The relationship between age-related genetic factors and health conditions has become a pivotal focus in aging research, particularly as the World Health Organization (WHO) delineates the leading global causes of mortality. However, the direct impact of age-related genes on the leading cause of death remains poorly understood. To investigate this gene-aging relationship, we analyzed protein-protein interactions using gene set enrichment analysis (GSEA) of a set of 307 age-related genes previously curated. The results indicated significant associations with 113 diverse disease categories, while adhering to a stringent false discovery rate (FDR) threshold of less than 1 x 10-5. Due to the difficulties in aligning the disease categories with WHOs leading causes of death, we reclassified the WHO categories using the more precise nomenclature specified in the 11th Revision of the International Classification of Diseases (ICD-11). The age-related genes account for the leading causes of death, with the exceptions being two infectious communicable diseases, tuberculosis and COVID-19. They impact the cardiovascular system, brain, lungs, and the whole body, while this study could not identify death by aging, which is not a well-defined medical cause of death. Furthermore, we identified a set of 15 recurring genes shared among multiple diseases, including TNF, AKT1, IL6, CDK2A, APOE, and TP53. This gene set was enriched for several disease categories, including cancer, inflammatory diseases, metabolic disorders, and neurodegenerative diseases. Additionally, it shows significant enrichment in various biological categories, with the regulation of nitric oxide activity being the most prominent; other enriched categories include the regulation of microRNA, lipid and carbohydrate metabolism, smooth muscle cell proliferation, insulin signaling, and phosphatidylinositol-3 kinase (PI3K) signaling. The findings suggest that the recurring genes act as pleiotropic hubs, influencing multiple leading causes of death, while other genes are more specific to each disease category.

Aging involves a progressive decline in bodily functions, underscoring the need for interventions that enhance healthspan. In this study, we screened nine natural products in Caenorhabditis elegans using whole-organism phenotyping to assess mobility endpoints, and subsequently focused on curcumin, sulforaphane, and their combination. In replicated follow-up experiments, all three interventions improved late-adult mobility after Day 2 of adulthood. Sulforaphane and the combination provided the strongest gains, whereas curcumin showed a distinct benefit profile, with more pronounced effects on time active measures than on speed-based metrics. To examine associated molecular changes, we performed transcriptomic profiling on Day 3 adults. Curcumin was associated with lipid and sphingolipid remodeling together with reduced expression of several innate immune effectors, whereas sulforaphane induced glutathione-linked detoxification signatures involving multiple gst genes. The combination retained major features of both single-compound responses while adding combination-specific changes that broadened detoxification-associated signatures and extended repression of lectin-and lysozyme-associated genes. Transcription factor activity inference further supported SKN-1-linked detoxification responses under sulforaphane and the combination. Overall, these results suggest that curcumin and sulforaphane engage distinct yet partially convergent maintenance-related programs, and that their combination broadens the underlying molecular response without producing additive mobility gains. These findings motivate further testing of natural product combinations in healthspan-related contexts.

Biological aging clocks are typically evaluated through competitive benchmarking, implicitly assuming that a single metric can sufficiently capture the complexities of aging1-6. Here, we tested an alternative hypothesis: that distinct clock types capture orthogonal dimensions of aging and therefore yield greater value when integrated. Using the Framingham Heart Study, we compared the immune-aging metric, IMM-AGE, with established DNA methylation clocks and found that integrated models consistently outperformed single-clock approaches. To investigate the basis of this complementarity, we derived IMMAGE-Epi, a 22-CpG methylation surrogate of IMM-AGE which exhibited minimal overlap with canonical epigenetic clock CpGs, suggesting that immune aging is associated with a distinct methylomic feature and pathway space rather than representing a reformulation of existing clock architectures. Together, our findings support an emerging multidimensional model of biological aging in which integrating orthogonal biological clocks may offer greater translational utility than competitive single-clock optimization.

Type 2 diabetes (T2D) arises from distinct diabetogenic mechanisms, but whether these mechanisms differ in their associations with hallmarks of aging remains unclear. We analyzed 449,505 UK Biobank and 374,973 All of Us participants using an overall T2D polygenic score (oPS) and eight partitioned polygenic scores (pPSs) representing distinct T2D-related mechanisms. Across organ systems, 81 age-related diseases were assigned to nine hallmarks of aging. UK Biobank analyses used Cox regression for incident hallmark-level outcomes, and All of Us analyses used logistic regression for prevalent hallmark-level outcomes. In both cohorts, the oPS was associated with disease burden across hallmarks, whereas pPS associations varied by mechanism. The obesity pPS showed the strongest and most consistent associations, while other insulin-resistance-related pPSs, including the lipodystrophy pPS, showed more modest positive associations. Beta-cell dysfunction pPS associations were close to null across hallmarks. Obesity pPS-hallmark associations were significantly attenuated after adjustment for BMI, and lipodystrophy pPS-hallmark associations after adjustment for triglyceride-to-HDL cholesterol ratio (TG/HDL-C), a marker of insulin resistance. These findings suggest that adiposity and insulin resistance, indexed by BMI and TG/HDL-C, may act as modifiable factors in the T2D genetic burden on aging hallmarks.

BackgroundSkin aging is multifactorial, and finished multi-ingredient oral beauty supplements require dedicated clinical evaluation because their effects cannot be inferred from individual ingredient data alone. ObjectiveTo explore, in a 56-day single-arm open-label study, whether daily oral intake of NatureU(R) Mind Care BeautyU Caps is associated with within-participant changes in crows-feet wrinkle count (primary endpoint), stratum corneum hydration (secondary endpoint), and additional exploratory skin-aging parameters in adult women. MethodsA single-center, open-label, single-arm exploratory study enrolled 33 healthy women aged 36-56 years; 31 completed the protocol and were included in the completer efficacy analysis. Participants took one capsule orally once daily for 56 consecutive days. Assessments were performed at D0, D28 and D56 using PRIMOS CR, Corneometer CM 825, Cutometer MPA580, Glossymeter, Colorimeter CL400, Mexameter MX18, VISIA CR, DermaScan and a structured self-assessment. ResultsPRIMOS CR crows-feet wrinkle count fell from 965 {+/-} 334 at D0 to 514 {+/-} 171 at D56 (within-participant change -46.74%; nominal P = 0.001). Corneometer hydration rose from 44.3 {+/-} 7.8 to 70.3 {+/-} 9.9 (+58.69%; nominal P = 0.001). Exploratory parameters (other wrinkle metrics, elasticity, gloss, ITA{degrees}, melanin, spots, dermal thickness/density) generally moved in directions consistent with the primary signal. No adverse reactions were reported. ConclusionIn this open-label, single-arm exploratory study, daily NatureU(R) Mind Care BeautyU Caps was associated with within-participant reductions in crows-feet wrinkle count and increases in stratum corneum hydration over 56 days. Findings are hypothesis-generating; randomized placebo-controlled trials are required.

Proliferating cells can enter an irreversible state of cell-cycle arrest known as cellular senescence. The accumulation of senescent cells contributes to organismal ageing and age-related pathologies. Consequently, therapeutic strategies have emerged to selectively eliminate senescent cells (senolytics). Our previous work suggested that senescent mouse myoblasts are more susceptible to reductive stress-induced cell death than proliferating cells. Here, we replicated these findings in human LHCN-M2 myoblasts, demonstrating a biphasic dose-response relationship with cell death, wherein low concentrations were associated with reduced cell death in both proliferating and senescent cells, whereas higher concentrations selectively induced cytotoxicity in senescent cells. We propose that many identified natural senolytic compounds may exert their in vitro activity, at least in part, through the induction of reductive stress due to their antioxidant properties. These findings have important implications for understanding senolytic mechanisms and guiding the future development of senescence-targeting therapies.

Aging is accompanied by a progressive decline in physiological function that contributes to chronic disease development. Biological clocks estimated from high-dimensional clinical and biological measurements may provide more granular tracking of the aging processes. Current biological clocks, however, have limited cross-ancestry generalizability and clinical applicability. Here, we developed a multi-ancestry biological clock (ClinBAG) using 22 routine blood and anthropometric biomarkers in 14,328 age- and sex-balanced individuals from the All of Us Research Program. We tested the association of ClinBAG with 434 traits and evaluated its ability to predict incident disease in 152,733 non-overlapping individuals. We also conducted genome-wide association studies in European (N=74,675), African (N=22,315), and Admixed American ancestry individuals (N=19,940). Among 190 neurological phenotypes, elevated ClinBAG was associated with cognitive decline, increased incidence of dementia (HR=1.020, p=1.6x10-5) and Parkinson's disease (HR=1.014, p=0.023), and decreased risk of migraine (HR=0.991, p=8.7x10-4). We also identified common (NPRL3) and ancestry-specific genetic loci (HBB in African-ancestry and FADS1/FADS2 in European-ancestry) for ClinBAG. Single-cell enrichment revealed that ClinBAG-associated genes are overexpressed in double-negative (DN) T cells in an age-dependent manner. This study presents a clinically applicable multi-ancestry biological age clock predicting neurological disease risk. Our findings also uncover population-specific genetic drivers, particularly involving erythropoiesis and DN T-cell-mediated neuroinflammation.

Aging is the primary driver of chronic disease and mortality, requiring comprehensive frameworks for quantification of aging and nomination of longevity interventions. We developed mAge (multimodal age), a biological aging framework that integrates plasma proteomics, wearables, and mortality hazard to predict biological age, intrinsic capacity, and mortality risk. By combining proteomic and wearable data in UK Biobank samples, mAge exceeds unimodal baseline age prediction to 0.87 test R{superscript 2} and 2.3 years mean error, and reduces unimodal baseline mortality prediction error by 21%. We further constructed organ-and cell type-specific biological clocks that quantify aging across 49 distinct subsystems, revealing that cardiac, immune, and intracellular protein signatures benefit most from wearable integration. By mapping data to FDA-approved drug targets, we identified interventions, such as GLP-1 receptor agonists, gabapentin, and ACE inhibitors, that are associated with lower overall and subsystem-specific proteomic age and mortality risk or are associated with longer time-to-death and later age-at-death in longitudinal and deceased cohorts. mAge establishes a scalable framework for nominating and validating personalized longevity interventions, bridging continuous digital monitoring with molecular aging diagnostics.

Centenarians exhibit marked heterogeneity in biological aging despite their exceptional longevity. To identify biological factors linked to survival at extreme old age, we examined DNA methylation-based measures of aging in 247 cognitively healthy Dutch centenarians using PacBio long-read methylation sequencing. Age acceleration derived from the DNA methylation clock GrimAge emerged as a robust predictor of mortality (HR = 1.60, 95% CI: 1.28-2.00), independent of markers previously associated with mortality in centenarians, such as Mini-Mental State Examination (MMSE) scores (HR = 0.68, 95% CI: 0.56-0.84) and plasma neurofilament light chain (NfL) levels (HR = 1.29, 95% CI: 1.09-1.53). GrimAge acceleration showed limited association with phenotypes related to brain aging, including cognitive performance, neurodegeneration- and Alzheimers disease-related plasma biomarkers, and neuropathological measures. By contrast, it was associated with hematological markers consistent with age-related myeloid shift, although these did not fully account for its association with survival. Together, these findings suggest that GrimAge reflects a mortality-associated dimension of aging that is distinct from brain aging and remains informative even at extreme old age.

A central challenge in computational geroscience is to distinguish molecular quantities that predict mortality from those that causally drive it. Epigenetic clocks and aging biomarkers are increasingly used as if they were that mechanism, yet this is rarely tested directly. This distinction also bears on competing theories of aging: damage/reliability (A), hyperfunction/mTOR-IIS (B-1), and information loss (B-2). Although individual aging proteins have been tested piecemeal, no study has asked, in one framework, what fraction of mortality is measurable, whether it is causal, and whether it is reversible. Using only public, de-identified data, we evaluate this three ways. First, a Markov generator-matrix model of hallmark-load dynamics with death as an absorbing state, fitted by Bayesian inference through a joint biomarker-and-mortality likelihood to NHANES with linked mortality (n=23,844) and replicated in the Health and Retirement Study (HRS), decomposes Gompertz acceleration into visible (measured-biomarker-driven) and latent components. Second, a positive-control-calibrated, two-platform cis-pQTL Mendelian-randomization and colocalization design (UKB-PPP, deCODE) against parental-lifespan GWAS tests whether the latent's measurable components are causal. Third, a clock battery (Horvath, chronological; DamAge, causality-enriched damage) tests reversibility in cellular reprogramming. Within the model, ~92% of Gompertz acceleration is assigned to a latent component not captured by measured blood-biomarker axes (NHANES 92.5%, HRS 91.6%); the latent is partly encoded in DNA-methylation signatures but not transcription. The known causal proteins are detected (LPA p=9x10-12; IL6R p=2.8x10-5), yet the latent's components, across inflammatory, renal and growth-signalling (IGFBP3, IGF-1) axes, are null and do not colocalize on either platform. Reprogramming reverses the chronological clock (-11 to -22 yr) but not the causality-enriched damage clock. The model-inferred mortality-driving component is largely latent to accessible biomarkers; its measurable molecular proxies show no supported causal effect where the design detects known causes; and the causality-enriched damage-clock signal is resistant to partial reprogramming.

Motivational changes are determinants of healthy aging, social engagement, and functional independence, and may signal early neurodegenerative risk. Existing assessment approaches in aging typically treat motivation as a unitary construct. Here, we introduce MotDem, an age-appropriate measure of motivation co-designed with people living with dementia, carers, and clinicians. Across a broad adult lifespan sample (18-80 years), MotDem revealed a robust three-domain motivational architecture encompassing goal-directed behaviour, social reward, and pleasure, with a fourth satiety factor retained as exploratory. This structure was replicated in an independent older cohort (45-80 years) from a different national context. MotDem showed strong convergence with established measures of apathy and anhedonia, alongside more modest associations with depressive symptomatology. Together, these findings show that motivational aging is multifaceted and poorly captured by traditional unitary assessment. MotDem provides a multidimensional framework for measuring distinct motivational drivers of heterogeneous aging trajectories, with implications for resilience, wellbeing, and neurodegenerative risk.

IntroductionLife expectancy for people with type 1 diabetes has increased due to improved treatment of diabetes and its comorbidities, allowing many to reach old age. Still, we lack knowledge of how individuals with type 1 diabetes age. On one hand, those who reach older age can be considered survivors, but on the other hand their long-standing diabetes might still exhibit negative impacts on their health and functional ability. Healthy ageing is the World Health Organizations priority for this decade. The focus has shifted from chronological age to functional ability, which reflects the ability of individuals to perform meaningful activities. Functional ability is shaped by intrinsic capacity, the environment, and their interaction. Intrinsic capacity encompasses five main domains: cognition, vitality, sensory function, locomotion, and psychological domain. This observational study aims to assess how this vulnerable group of individuals with type 1 diabetes age and to identify factors that contribute to their healthy ageing, intrinsic capacity, and its domains. Methods and analysisThe FinnDiane LifeOne Study is a prospective observational cohort study. We aim to recruit a minimum of 300 individuals with type 1 diabetes from the FinnDiane Study, aged >65, and a minimum of 100 matched controls without insulin-dependent diabetes. The cohort will be comprehensively characterized, including clinical assessment, laboratory tests, questionnaires, and a geriatric assessment of different aspects of functioning ability, with five years intervals. We will compare the individuals with type 1 diabetes to their matched controls. For those with type 1 diabetes, we will further assess which factors from the FinnDiane baseline and trajectories during follow-up predict healthy ageing in above 65-year-olds. Ethics and disseminationThe LifeOne study protocol is approved by the Ethics Committee of HUS Helsinki University Hospital (HUS/4387/2023) and the study adheres to the Declaration of Helsinki. Written informed consent is obtained from each participant. Findings will be published in international peer-reviewed journals with an open access choice. The study is registered at ClinicalTrials.gov with ID NCT07289204. STRENGTHS AND LIMITATIONS OF THE STUDYO_LIThis is a prospective observational cohort study with a matched control group. C_LIO_LIFor the participants with type 1 diabetes, we have unique and comprehensive longitudinal clinical and genetic data available from approximately participants middle age, enabling identification of factors that contribute to their healthy ageing, while accounting for the competing risk of death. C_LIO_LIThe cohort is thoroughly characterised regarding diabetes, cardiometabolic health, lifestyle, psychosocial factors, and includes a geriatric assessment, thereby enabling comparison of impact of ageing between individuals with type 1 diabetes and controls without insulin-dependent diabetes. C_LIO_LIThe cohort is Caucasian with recruitment from Southern Finland, potentially limiting generalisability to other more ethnically diverse populations. C_LI

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSDeclines in function occur in both "normal" aging (in the absence of disease) and age-related pathological contexts, like Alzheimers disease (AD). Whether "anti-aging" interventions (that extend lifespan) also promote cognitive function in aging and AD remains unexplored. METHODSWe assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice. RESULTSIn mid-aged and aged Ntg-HET3 mice, acarbose treatment resulted in performance equivalent to young adults. Conversely, acarbose failed to ameliorate age-related deficits in 5xFAD-HET3 mice. DISCUSSIONThis work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it reinforces that AD is not simply accelerated aging and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.

Genome-wide association studies have identified risk loci for aging brain disorders, but mechanistic interpretation depends on linking these loci to genes and to the tissues, cell types, and molecular modalities in which those genes act. Here we introduce FunGen-xQTL Multi-Brain (FGMB), a multi-context regulome-wide association atlas for transcriptome-wide association studies (TWAS) built from molecular datasets assembled by the ADSP Functional Genomics Consortium. FGMB provides cis-genetic prediction models for 17,375 protein-coding genes across 36 molecular datasets, 18 contexts, and 3 regulatory modalities, yielding more than 293,000 imputable gene-level or splice-event models. FGMB evaluates eight established and newer Bayesian or multivariate prediction methods, including cross-context models that borrow information across tissues and cell types. Applied to Alzheimer's disease, FGMB identified 327 TWAS associations and used joint fine-mapping of variants and predicted molecular traits to prioritize 146 gene--molecular-trait pairs, distinguishing regulatory associations from linkage disequilibrium (LD) hitchhiking.

BackgroundThe continuous rise in life expectancy introduces a central challenge of new longevity, ensuring that the additional years gained are accompanied by the preservation of cognitive function and quality. MethodsWe propose a modeling framework for multi-domain brain age derived from a repertoire of digital cognitive metrics. The model, based on Ridge regression with Leave-One-Out cross-validation, was trained in a cohort of 394 healthy controls (HC; 307 women and 87 men; mean age 30.0 {+/-} 12.5 years; range 17-64). ResultsThe model achieved a correlation between chronological age and predicted age of r = 0.942 with a mean absolute error of 3.05 years. When applied to three additional clinical cohorts, multiple sclerosis (N = 70), traumatic brain injury (N = 23), and depression (N = 18), the model detected significant accelerated cognitive aging across all conditions, with processing speed emerging as the dominant contributor to accelerated aging, albeit with varying degrees of concentration across pathologies. ConclusionsDigital cognitive metrics provide an accessible, non-invasive, and scalable biomarker for tracking brain aging, with strong potential for informing personalized neuropsychological interventions and for integration into active aging frameworks within the context of modern longevity.

Immune decline in older adults is associated with increased susceptibility to infection and chronic inflammatory diseases. Macrophages are critical innate immune cells that show reduced capacity for phagocytosis and migration with age. Our previous work shows that reduced levels of MYC and USF1 transcription factors are drivers of macrophage age-related functional decline. Here we show that macrophage-specific Myc overexpression improves macrophage migration and, more importantly, is able to improve physical performance at older age in Drosophila, while lifespan remains unaffected. Treatment of human primary macrophages from older individuals with the geroprotective supplement fisetin reverses the decline in MYC expression and improves phagocytosis of pathogens and cell migration functions towards levels seen in younger individuals. Mechanistically, fisetin acts via MYC, by restoring expression levels of MYC targets in human macrophages that are altered with age. Finally, fisetin feeding in older mice improves motor activity and reduces frailty, as well as restoring primary macrophage function and Myc expression in vitro. These findings reveal that restoration of MYC in macrophage ageing is responsible, at least in part, for improvement in physical performance with age and identify this pathway as a rational target to reverse age-related immune decline. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/731325v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1a1935org.highwire.dtl.DTLVardef@16d2119org.highwire.dtl.DTLVardef@197f838org.highwire.dtl.DTLVardef@294839_HPS_FORMAT_FIGEXP M_FIG C_FIG

Psychedelic compounds such as lysergic acid diethylamide (LSD) are increasingly studied for their neuroplastic effects and potential relevance to brain aging and neurodegeneration. However, the molecular mechanisms linking psychedelic-induced plasticity to age-associated cognitive decline remain unclear. Brain aging and dementia are characterized by coordinated transcriptional programs that underlie synaptic dysfunction and altered neuron-glia interactions. If psychedelic-induced plasticity engages opposing molecular programs, it could counteract these conserved trajectories. In computational drug discovery, this concept has been formalized as the principle of transcriptional signature reversal, whereby compounds inducing gene expression states opposite to disease-associated programs may exert a therapeutic effect by counteracting disease-associated phenotypes. Here, we combine cross-species transcriptomic analyses with experimental validation to test whether LSD opposes conserved signatures of brain aging and dementia. By comparing transcriptional profiles induced by chronic LSD treatment in rodents with age- and dementia-associated gene expression changes in the human prefrontal cortex, we show that LSD induces gene expression patterns strongly anti-correlated with aging and neurodegeneration programs. This reversal is specific compared to other pharmacological perturbations and is reproducible across datasets and species. Moreover, LSD counteracts amyloid-{beta}-induced structural and molecular alterations in primary cortical neurons, linking transcriptomic opposition to functional rescue under neurodegenerative stress. Together, our findings suggest that LSD modulates molecular and cellular pathways associated with brain aging and neurodegeneration, linking systems-level gene expression changes to structural and functional resilience in neurodegeneration-relevant contexts.