The companion dog as a model for inflammaging: a cross-sectional pilot study.

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging.

Clippers are superior to scissors in the collection of hair for chemical analysis in companion dogs: a Dog Aging Project preliminary study.

OBJECTIVE: To identify the safest, most efficient method for hair sample collection from companion dogs among clippers, scissors, and razors and to validate obtained samples with cortisol concentration analysis. ANIMALS: 25 healthy, privately owned dogs. METHODS: 2 hair samples were collected from each dog's ischiatic region with different implements (scissors, razors, or clippers). The collecting clinician completed a Hair Collection Questionnaire (HCQ) for each sample that compared subjective sample quality, time of collection, restraint needed, and patient experience. Each sample was evaluated by cortisol enzyme immunoassay. RESULTS: Clippers had higher overall HCQ scores than scissors, and scissors had higher HCQ scores than razors. Collection was faster for clippers than scissors, and scissors were faster than razors. There were no differences in sample quality between scissors and clippers, and sample quality was lower with razors. There was no difference in restraint needed or patient experience. Collection of long hair had higher HCQ scores than collection of medium and short hair. Collection of hair from dogs with an undercoat had higher HCQ scores than collection of hair from dogs without an undercoat. Dog size had no effect on HCQ score. Hair cortisol concentration did not vary between scissors or clippers (P = .111). Hair color and age did not affect hair cortisol concentration (P = .966 and P = .676, respectively). CLINICAL RELEVANCE: Clippers are recommended for hair sample collection from companion dogs. Scissors are an adequate alternative.

Natural Variation in Age-Related Dopamine Neuron Degeneration is Glutathione-Dependent and Linked to Life Span.

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Naturally short-lived strains exhibit a loss of dopamine neurons but not generalized neurodegeneration, while long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress and vulnerability to silencing the familial PD gene parkin . Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (GCL) overexpression is sufficient to normalize ROS levels, extend life span and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is frequently reported in idiopathic PD patient brain. Building on this evidence, we detect reduced levels of GCL catalytic and modulatory subunits in brain from PD patients harboring the LRRK2 G2019S mutation, implicating possible glutathione deficits in familial LRRK2-linked PD. Our study across Drosophila and human PD systems suggests that glutathione plays an important role in the influence of aging on PD neurodegeneration.

DNA methylation and chromatin accessibility predict age in the domestic dog.

Across mammals, the epigenome is highly predictive of chronological age. These "epigenetic clocks," most of which have been built using DNA methylation (DNAm) profiles, have gained traction as biomarkers of aging and organismal health. While the ability of DNAm to predict chronological age has been repeatedly demonstrated, the ability of other epigenetic features to predict age remains unclear. Here, we use two types of epigenetic information-DNAm, and chromatin accessibility as measured by ATAC-seq-to develop age predictors in peripheral blood mononuclear cells sampled from a population of domesticated dogs. We measured DNAm and ATAC-seq profiles for 71 dogs, building separate predictive clocks from each, as well as the combined dataset. We also use fluorescence-assisted cell sorting to quantify major lymphoid populations for each sample. We found that chromatin accessibility can accurately predict chronological age (R2 ATAC = 26%), though less accurately than the DNAm clock (R2 DNAm = 33%), and the clock built from the combined datasets was comparable to both (R2 combined = 29%). We also observed various populations of CD62L+ T cells significantly correlated with dog age. Finally, we found that all three clocks selected features that were in or near at least two protein-coding genes: BAIAP2 and SCARF2, both previously implicated in processes related to cognitive or neurological impairment. Taken together, these results highlight the potential of chromatin accessibility as a complementary epigenetic resource for modeling and investigating biologic age.

Dog size and patterns of disease history across the canine age spectrum: Results from the Dog Aging Project.

Age in dogs is associated with the risk of many diseases, and canine size is a major factor in that risk. However, the size patterns are complex. While small size dogs tend to live longer, some diseases are more prevalent among small dogs. In this study we seek to quantify how the pattern of disease history varies across the spectrum of dog size, dog age, and their interaction. Utilizing owner-reported data on disease history from a substantial number of companion dogs enrolled in the Dog Aging Project, we investigate how body size, as measured by weight, associates with the lifetime prevalence of a reported condition and its pattern across age for various disease categories. We found significant positive associations between dog size and the lifetime prevalence of skin, bone/orthopedic, gastrointestinal, ear/nose/throat, cancer/tumor, brain/neurologic, endocrine, and infectious diseases. Similarly, dog size was negatively associated with lifetime prevalence of ocular, cardiac, liver/pancreas, and respiratory disease categories. Kidney/urinary disease prevalence did not vary by size. We also found that the association between age and lifetime disease prevalence varied by dog size for many conditions including ocular, cardiac, orthopedic, ear/nose/throat, and cancer. Controlling for sex, purebred vs. mixed-breed status, and geographic region made little difference in all disease categories we studied. Our results align with the reduced lifespan in larger dogs for most of the disease categories and suggest potential avenues for further examination.

The neuropeptide drosulfakinin enhances choosiness and protects males from the aging effects of social perception.

The motivation to reproduce is a potent natural drive, and the social behaviors that induce it can severely impact animal health and lifespan. Indeed, in Drosophila males, accelerated aging associated with reproduction arises not from the physical act of courtship or copulation but instead from the motivational drive to court and mate. To better understand the mechanisms underlying social effects on aging, we studied male choosiness for mates. We found that increased activity of insulin-producing cells (IPCs) of the fly brain potentiated choosiness without consistently affecting courtship activity. Surprisingly, this effect was not caused by insulins themselves, but instead by drosulfakinin (DSK), another neuropeptide produced in a subset of the IPCs, acting through one of the two DSK receptors, CCKLR-17D1. Activation of Dsk+ IPC neurons also decreased food consumption, while activation of Dsk+ neurons outside of IPCs affected neither choosiness nor feeding, suggesting an overlap between Dsk+neurons modulating choosiness and those influencing satiety. Broader activation of Dsk+ neurons (both within and outside of the IPCs) was required to rescue the detrimental effect of female pheromone exposure on male lifespan, as was the function of both DSK receptors. The same broad set of Dsk+ neurons was found to reinforce normally aversive feeding interactions, but only after exposure to female pheromones, suggesting that perception of the opposite sex gates rewarding properties of these neurons. We speculate that broad Dsk+ neuron activation is associated with states of satiety and social experience, which under stressful conditions is rewarding and beneficial for lifespan.

Case report: Severe asymptomatic hypertriglyceridemia associated with long-term low-dose rapamycin administration in a healthy middle-aged Labrador retriever.

Rapamycin is an mTOR inhibitor that has been shown to extend the lifespan of laboratory model organisms. In humans, rapamycin is used at higher doses as an immunosuppressive medication to prevent organ rejection. Numerous adverse effects are seen with rapamycin treatment in humans, with one of the most common being dysregulation of lipid metabolism. In humans, this often manifests as mild to moderate serum lipid elevations, with a small subset developing extreme triglyceride elevations. This case report describes an eight-year-old, castrated male, clinically healthy Labrador retriever who developed severe hypertriglyceridemia associated with low-dose rapamycin administration over a six-month period. During this time, the dog was asymptomatic and displayed no other clinical abnormalities, aside from a progressive lipemia. Within 15 days of discontinuing rapamycin treatment, and with no targeted lipemic intervention, the dog's lipemia and hypertriglyceridemia completely resolved.

Cellular age explains variation in age-related cell-to-cell transcriptome variability.

Organs and tissues age at different rates within a single individual. Such asynchrony in aging has been widely observed at multiple levels, from functional hallmarks, such as anatomical structures and physiological processes, to molecular endophenotypes, such as the transcriptome and metabolome. However, we lack a conceptual framework to understand why some components age faster than others. Just as demographic models explain why aging evolves, here we test the hypothesis that demographic differences among cell types, determined by cell-specific differences in turnover rate, can explain why the transcriptome shows signs of aging in some cell types but not others. Through analysis of mouse single-cell transcriptome data across diverse tissues and ages, we find that cellular age explains a large proportion of the variation in the age-related increase in transcriptome variance. We further show that long-lived cells are characterized by relatively high expression of genes associated with proteostasis and that the transcriptome of long-lived cells shows greater evolutionary constraint than short-lived cells. In contrast, in short-lived cell types, the transcriptome is enriched for genes associated with DNA repair. Based on these observations, we develop a novel heuristic model that explains how and why aging rates differ among cell types.

Lifetime prevalence of owner-reported medical conditions in the 25 most common dog breeds in the Dog Aging Project pack.

Introduction: Large scale data on the prevalence of diverse medical conditions among dog breeds in the United States are sparse. This cross-sectional study sought to estimate the lifetime prevalence of medical conditions among US dogs and to determine whether purebred dogs have higher lifetime prevalence of specific medical conditions compared to mixed-breed dogs. Methods: Using owner-reported survey data collected through the Dog Aging Project (DAP) Health and Life Experience Survey for 27,541 companion dogs, we identified the 10 most commonly reported medical conditions in each of the 25 most common dog breeds within the DAP cohort. Lifetime prevalence estimates of these medical conditions were compared between mixed-breed and purebred populations. The frequency of dogs for whom no medical conditions were reported was also assessed within each breed and the overall mixed-breed and purebred populations. Results: A total of 53 medical conditions comprised the top 10 conditions for the 25 most popular breeds. The number of dogs for whom no medical conditions were reported was significantly different (p = 0.002) between purebred (22.3%) and mixed-breed dogs (20.7%). The medical conditions most frequently reported within the top 10 conditions across breeds were dental calculus (in 24 out of 25 breeds), dog bite (23/25), extracted teeth (21/25), osteoarthritis (15/25), and Giardia (15/25). Discussion: Purebred dogs in the DAP did not show higher lifetime prevalence of medical conditions compared to mixed-breed dogs, and a higher proportion of purebred dogs than mixed-breed dogs had no owner-reported medical conditions. Individual breeds may still show higher lifetime prevalence for specific conditions.

A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs.

Introduction: Geroscience studies of low-dose rapamycin in laboratory species have identified numerous benefits, including reversing age-related cardiac dysfunction. Cardiovascular benefits have been observed in dogs with 10 weeks of treatment, raising questions about possible benefits and adverse effects of long-term use of low-dose rapamycin. The objectives of this study were to assess the impact of 6 months of low-dose rapamycin on echocardiographic indices of cardiac function in healthy dogs and to document the occurrence of adverse events. Methods: Seventeen client-owned dogs aged 6-10 years, weighing 18-36 kg, and without significant systemic disease were included in a prospective, randomized, placebo-controlled, masked clinical trial. Low-dose rapamycin (0.025 mg/kg) or placebo was administered three times per week for 6 months. Baseline, 6-month, and 12-month evaluation included physical examination, cardiology examination, and clinicopathology. Three-month evaluation included physical examination and clinicopathology. Owners completed online questionnaires every 2 weeks. Results: There were no statistically significant differences in echocardiographic parameters between rapamycin and placebo groups at 6 or 12 months. No clinically significant adverse events occurred. In 26.8% of the bi-weekly surveys owners whose dogs received rapamycin reported perceived positive changes in behavior or health, compared to 8.1% in the placebo group (p = 0.04). Discussion: While no clinically significant change in cardiac function was observed in dogs treated with low-dose rapamycin, the drug was well-tolerated with no significant adverse events.

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity.

Alzheimer's disease is characterized by 2 pathological proteins, amyloid beta 42 and tau. The majority of Alzheimer's disease cases in the population are sporadic and late-onset Alzheimer's disease, which exhibits high levels of heritability. While several genetic risk factors for late-onset Alzheimer's disease have been identified and replicated in independent studies, including the ApoE ε4 allele, the great majority of the heritability of late-onset Alzheimer's disease remains unexplained, likely due to the aggregate effects of a very large number of genes with small effect size, as well as to biases in sample collection and statistical approaches. Here, we present an unbiased forward genetic screen in Drosophila looking for naturally occurring modifiers of amyloid beta 42- and tau-induced ommatidial degeneration. Our results identify 14 significant SNPs, which map to 12 potential genes in 8 unique genomic regions. Our hits that are significant after genome-wide correction identify genes involved in neuronal development, signal transduction, and organismal development. Looking more broadly at suggestive hits (P < 10-5), we see significant enrichment in genes associated with neurogenesis, development, and growth as well as significant enrichment in genes whose orthologs have been identified as significantly or suggestively associated with Alzheimer's disease in human GWAS studies. These latter genes include ones whose orthologs are in close proximity to regions in the human genome that are associated with Alzheimer's disease, but where a causal gene has not been identified. Together, our results illustrate the potential for complementary and convergent evidence provided through multitrait GWAS in Drosophila to supplement and inform human studies, helping to identify the remaining heritability and novel modifiers of complex diseases.

How size and genetic diversity shape lifespan across breeds of purebred dogs.

While the lifespan advantage of small body size and mixed breed status has been documented repeatedly, evidence for an effect of genetic diversity across dog breeds is equivocal. We hypothesized that this might be due to a strong right-censoring bias in available breed-specific lifespan estimates where early-dying dogs from birth cohorts that have not died off completely at the time of data collection are sampled disproportionately, especially in breeds with rapidly growing populations. We took advantage of data on owner reported lifespan and cause of death from a large public database to quantify the effect of size and genetic diversity (heterozygosity) on mortality patterns across 118 breeds based on more than 40,000 dogs. After documenting and removing the right-censoring bias from the breed-specific lifespan estimates by including only completed birth cohorts in our analyses, we show that small size and genetic diversity are both linked to a significant increase in mean lifespan across breeds. To better understand the proximate mechanisms underlying these patterns, we then investigated two major mortality causes in dogs - the cumulative pathophysiologies of old age and cancer. Old age lifespan, as well as the percentage of old age mortality, decreased with increasing body size and increased with increasing genetic diversity. The lifespan of dogs dying of cancer followed the same patterns, but while large size significantly increased proportional cancer mortality, we could not detect a significant signal for lowered cancer mortality with increasing diversity. Our findings suggest that outcross programs will be beneficial for breed health and longevity. They also emphasize the need for high-quality mortality data for veterinary epidemiology as well as for developing the dog as a translational model for human geroscience.

Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project.

Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions.

Demographic factors associated with joint supplement use in dogs from the Dog Aging Project.

Osteoarthritis (OA) is one of the most prevalent age-related chronic conditions that afflict companion dogs, and multiple joint supplements are available to prevent or treat OA, though the efficacy of these treatments is controversial. While the demographic factors that are associated with OA diagnosis are well established, the factors that are associated with joint supplement use are not as well studied. Using data collected from the Dog Aging Project, we analyzed owner survey responses regarding joint supplement administration and OA diagnosis for 26,951 adult dogs. In this cross-sectional analysis, logistic regression models and odds-ratios (OR) were employed to determine demographic factors of dogs and their owners that were associated with joint supplement administration. Forty percent of adult dogs in our population were given some type of joint supplement. Perhaps not surprisingly, dogs of older age, larger size, and those that were ever overweight were more likely to receive a joint supplement. Younger owner age, urban living, owner education, and feeding commercial dry food were associated with a reduced likelihood of administration of joint supplements to dogs. Interestingly, mixed breed dogs were also less likely to be administered a joint supplement (OR: 0.73). Dogs with a clinical diagnosis of OA were more likely to receive a joint supplement than those without a reported OA diagnosis (OR: 3.82). Neutered dogs were more likely to have a diagnosis of OA, even after controlling for other demographic factors, yet their prevalence of joint supplement administration was the same as intact dogs. Overall, joint supplement use appears to be high in our large population of dogs in the United States. Prospective studies are needed to determine if joint supplements are more commonly administered as a preventative for OA or after an OA clinical diagnosis.

In search of a Drosophila core cellular network with single-cell transcriptome data.

Along with specialized functions, cells of multicellular organisms also perform essential functions common to most if not all cells. Whether diverse cells do this by using the same set of genes, interacting in a fixed coordinated fashion to execute essential functions, or a subset of genes specific to certain cells, remains a central question in biology. Here, we focus on gene coexpression to search for a core cellular network across a whole organism. Single-cell RNA-sequencing measures gene expression of individual cells, enabling researchers to discover gene expression patterns that contribute to the diversity of cell functions. Current efforts to study cellular functions focus primarily on identifying differentially expressed genes across cells. However, patterns of coexpression between genes are probably more indicative of biological processes than are the expression of individual genes. We constructed cell-type-specific gene coexpression networks using single-cell transcriptome datasets covering diverse cell types from the fruit fly, Drosophila melanogaster. We detected a set of highly coordinated genes preserved across cell types and present this as the best estimate of a core cellular network. This core is very small compared with cell-type-specific gene coexpression networks and shows dense connectivity. Gene members of this core tend to be ancient genes and are enriched for those encoding ribosomal proteins. Overall, we find evidence for a core cellular network in diverse cell types of the fruit fly. The topological, structural, functional, and evolutionary properties of this core indicate that it accounts for only a minority of essential functions.

Systemic lipolysis promotes physiological fitness in Drosophila melanogaster.

Since interventions such as caloric restriction or fasting robustly promote lipid catabolism and improve aging-related phenotypical markers, we investigated the direct effect of increased lipid catabolism via overexpression of bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila, on lifespan and physiological fitness. Comprehensive characterization was carried out using RNA-seq, lipidomics and metabolomics analysis. Global overexpression of bmm strongly promoted numerous markers of physiological fitness, including increased female fecundity, fertility maintenance, preserved locomotion activity, increased mitochondrial biogenesis and oxidative metabolism. Increased bmm robustly upregulated the heat shock protein 70 (Hsp70) family of proteins, which equipped the flies with higher resistance to heat, cold, and ER stress via improved proteostasis. Despite improved physiological fitness, bmm overexpression did not extend lifespan. Taken together, these data show that bmm overexpression has broad beneficial effects on physiological fitness, but these effects did not impact lifespan.

Age and Physical Activity Levels in Companion Dogs: Results From the Dog Aging Project.

While there has been an abundance of studies on the important relationship between physical activity and age in both dogs and humans, studies on dogs have primarily focused on how a dog's biological characteristics, such as their weight, affect the age-activity relationship. To date, there is little knowledge about how this relationship may be associated with contextual- and owner-level characteristics. We leveraged a large and novel data set from the Dog Aging Project (DAP) to investigate the extent to which the age-activity relationship is associated with certain dog and owner characteristics, namely dog size, owner age, and the environment in which they live. Dogs are a unique model for aging research as they are exposed to similar social and environmental elements as humans but have a shorter life span, allowing researchers to observe their entire life course. We find that older dogs are less active than younger dogs; rural dogs are more active than suburban and urban dogs, especially at younger ages; and larger dogs are more active than smaller dogs. These findings are generally consistent with previous studies. However, a surprising finding is that older owners have more active dogs than younger owners. As one of the first studies to utilize the large survey data from the DAP, this study lays the foundation for future investigations to further understand and identify the biological, social, and environmental causes, as well as consequences, of aging.

Predictive Modeling of Alzheimer's and Parkinson's Disease Using Metabolomic and Lipidomic Profiles from Cerebrospinal Fluid.

In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing patients with Alzheimer's disease (AD), Parkinson's disease (PD), and healthy age-matched controls. We emphasize several statistical challenges associated with metabolomic studies where the number of measured metabolites far exceeds sample size. We found strong separation in the metabolome between PD and controls, as well as between PD and AD, with weaker separation between AD and controls. Consistent with existing literature, we found alanine, kynurenine, tryptophan, and serine to be associated with PD classification against controls, while alanine, creatine, and long chain ceramides were associated with AD classification against controls. We conducted a univariate pathway analysis of untargeted and targeted metabolite profiles and find that vitamin E and urea cycle metabolism pathways are associated with PD, while the aspartate/asparagine and c21-steroid hormone biosynthesis pathways are associated with AD. We also found that the amount of metabolite missingness varied by phenotype, highlighting the importance of examining missing data in future metabolomic studies.

KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.

Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.