Human Ageing Genomic Resources: updates on key databases in ageing research.

Ageing is a complex and multifactorial process. For two decades, the Human Ageing Genomic Resources (HAGR) have aided researchers in the study of various aspects of ageing and its manipulation. Here, we present the key features and recent enhancements of these resources, focusing on its six main databases. One database, GenAge, focuses on genes related to ageing, featuring 307 genes linked to human ageing and 2205 genes associated with longevity and ageing in model organisms. AnAge focuses on ageing, longevity, and life-history across animal species, containing data on 4645 species. DrugAge includes information about 1097 longevity drugs and compounds in model organisms such as mice, rats, flies, worms and yeast. GenDR provides a list of 214 genes associated with the life-extending benefits of dietary restriction in model organisms. CellAge contains a catalogue of 866 genes associated with cellular senescence. The LongevityMap serves as a repository for genetic variants associated with human longevity, encompassing 3144 variants pertaining to 884 genes. Additionally, HAGR provides various tools as well as gene expression signatures of ageing, dietary restriction, and replicative senescence based on meta-analyses. Our databases are integrated, regularly updated, and manually curated by experts. HAGR is freely available online (https://genomics.senescence.info/).

Effect of Aggregation and Molecular Size on the Ice Nucleation Efficiency of Proteins.

Aerosol acts as ice-nucleating particles (INPs) by catalyzing the formation of ice crystals in clouds at temperatures above the homogeneous nucleation threshold (-38 °C). In this study, we show that the immersion mode ice nucleation efficiency of the environmentally relevant protein, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), occurs at temperatures between -6.8 and -31.6 °C. Further, we suggest that this range is controlled by the RuBisCO concentration and protein aggregation. The warmest median nucleation temperature (-7.9 ± 0.8 °C) was associated with the highest concentration of RuBisCO (2 × 10-1 mg mL-1) and large aggregates with a hydrodynamic diameter of ∼103 nm. We investigated four additional chemically and structurally diverse proteins, plus the tripeptide glutathione, and found that each of them was a less effective INP than RuBisCO. Ice nucleation efficiency of the proteins was independent of the size (molecular weight) for the five proteins investigated in this study. In contrast to previous work, increasing the concentration and degree of aggregation did not universally increase ice nucleation efficiency. RuBisCO was the exception to this generalization, although the underlying molecular mechanism determining why aggregated RuBisCO is such an effective INP remains elusive.

Trucks versus treks: The relative influence of motorized versus nonmotorized recreation on a mammal community.

Outdoor recreation is increasing rapidly on public lands, with potential consequences for wildlife communities. Recreation can induce shifts in wildlife activity and habitat use, but responses vary widely even within the same species, suggesting mitigating factors that remain poorly understood. Both the type of recreation-motorized or nonmotorized-and the distance of wildlife from human disturbance may be important in developing a general understanding of recreation impacts on wildlife and making more informed management decisions. We conducted a camera-trapping survey in the Colville National Forest (CNF) of northeastern Washington in the summers of 2019 and 2020. We collected ~11,000 trap nights of spatially extensive data on nine mid-large mammalian species, simultaneously recording the presence and activity patterns of motorized (primarily vehicles on roads) and nonmotorized (primarily hikers on trails) recreation and wildlife both along trails and roads and off trails and off roads (away from most recreation). We used diel overlap analysis, time lag analysis, and single-season single-species occupancy modeling to examine the impact of recreation on the focal species. Species temporally avoided recreationists either by shifting to more nocturnal hours or delaying return to recently used recreation sites. Most species also responded spatially by altering the use or the intensity of use of camera sites due to recreation, although both positive and negative associations with recreation were documented. Species responded to nonmotorized recreation (e.g., hikers on trails) more often than motorized recreation (e.g., vehicles on roads). Most effects of recreation extended off the trail or road, although in three instances the spatiotemporal response of species to recreation along trails/roads disappeared a short distance away from those features. Our work suggests that a better understanding of landscape-scale impacts of recreation, including fitness consequences, will require additional work to disentangle the effects of different types of recreation and estimate the effective distance at which wildlife responds. Moreover, these results suggest that quiet, nonconsumptive recreation may warrant increased attention from land managers given its potential to influence the spatiotemporal ecology of numerous species.

Distribution and connectivity of protected areas in the Americas facilitates transboundary conservation.

Large-scale anthropogenic changes to landscapes will cause species to move and shift their ranges against a backdrop of international political boundaries. Transboundary conservation efforts are therefore key to preserving intact and connected landscapes, particularly if such efforts can be implemented within the framework of protected area networks that provide for resiliency and persistence in the face of threats such as climate change. We studied the distribution, connectivity, and integrity of protected areas in regions near international borders within the Americas. We found that there is a greater proportion of land protected near vs. far from borders, with this effect extending approximately 125 km from the border. This trend was most pronounced when considering multiuse categories of protected areas in the analysis. We also found that there is greater connectivity of protected areas in border regions than more internally within countries, and relatively low rates of habitat loss within border-situated and internal protected areas. Our results indicate that protected area networks are larger and more connected if considered in a transboundary context and that efforts to conserve species and mitigate effects of long-term stressors like climate change will be most successful when planning includes neighboring countries. Despite a relative lack of attention to transboundary conservation in the Americas, our results suggest substantial opportunities for linking landscapes via a focus on international border regions and coordination across borders in protected areas management.

Human Ageing Genomic Resources: new and updated databases.

In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR's main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/).

Chemical cross-linking in the structural analysis of protein assemblies.

For decades, chemical cross-linking of proteins has been an established method to study protein interaction partners. The chemical cross-linking approach has recently been revived by mass spectrometric analysis of the cross-linking reaction products. Chemical cross-linking and mass spectrometric analysis (CXMS) enables the identification of residues that are close in three-dimensional (3D) space but not necessarily close in primary sequence. Therefore, this approach provides medium resolution information to guide de novo structure prediction, protein interface mapping and protein complex model building. The robustness and compatibility of the CXMS approach with multiple biochemical methods have made it especially appealing for challenging systems with multiple biochemical compositions and conformation states. This review provides an overview of the CXMS approach, describing general procedures in sample processing, data acquisition and analysis. Selection of proper chemical cross-linking reagents, strategies for cross-linked peptide identification, and successful application of CXMS in structural characterization of proteins and protein complexes are discussed.

Systematic analysis of the gerontome reveals links between aging and age-related diseases.

In model organisms, over 2,000 genes have been shown to modulate aging, the collection of which we call the 'gerontome'. Although some individual aging-related genes have been the subject of intense scrutiny, their analysis as a whole has been limited. In particular, the genetic interaction of aging and age-related pathologies remain a subject of debate. In this work, we perform a systematic analysis of the gerontome across species, including human aging-related genes. First, by classifying aging-related genes as pro- or anti-longevity, we define distinct pathways and genes that modulate aging in different ways. Our subsequent comparison of aging-related genes with age-related disease genes reveals species-specific effects with strong overlaps between aging and age-related diseases in mice, yet surprisingly few overlaps in lower model organisms. We discover that genetic links between aging and age-related diseases are due to a small fraction of aging-related genes which also tend to have a high network connectivity. Other insights from our systematic analysis include assessing how using datasets with genes more or less studied than average may result in biases, showing that age-related disease genes have faster molecular evolution rates and predicting new aging-related drugs based on drug-gene interaction data. Overall, this is the largest systems-level analysis of the genetics of aging to date and the first to discriminate anti- and pro-longevity genes, revealing new insights on aging-related genes as a whole and their interactions with age-related diseases.

Using population-based routinely collected data from the Sentinel Stroke National Audit Programme to investigate factors associated with discharge to care home after rehabilitation.

OBJECTIVES: We investigated factors associated with Care Home (CH) discharge following stroke using routinely collected data in unselected patients and assessed the relevance of previous research findings to such patients seen in routine clinical practice. DESIGN: Retrospective analysis of data from the Sentinel Stroke National Audit Programme using univariate analysis and logistic regression. SETTING: A large acute and rehabilitation UK stroke unit with access to early supported discharge. SUBJECTS: All patients with stroke treated from 1 January 2014 to 1 January 2017. MAIN MEASURES: National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). RESULTS: Of 2584 patients (median age 78 years, interquartile range (IQR) 69-86; 50.6% male; 86.7% infarcts; median admission NIHSS 4, IQR 2-9), 401 (15.5%) died in hospital and 203 patients (7.9%) were permanently discharged to CH for the first time. Most had pre-discharge mRS scores of 4/5. Factors (odds ratios; 95% confidence intervals) associated with CH discharge included age (1.07; 1.05-1.10), incontinence (11.5; 7.13-19.25), dysphagia (2.13; 1.39-3.29), severe weakness (1.93; 1.28-2.92), pneumonia (1.68; 1.13-2.50), urinary tract infection (UTI) (1.70; 1.04-2.75) and depression (1.65; 1.00-2.72). In a subgroup of all patients with a pre-discharge mRS of 4/5, age (1.04; 1.02-1.06), incontinence (4.87; 2.39-11.02), UTI (2.0; 1.09-3.71) and pneumonia (1.59; 1.02-2.50) were the only factors associated with CH discharge. CONCLUSION: Potentially modifiable variables like incontinence, UTI and pneumonia were associated with CH discharge, particularly in the severely disabled.

Exopolymer production as a function of cell permeability and death in a diatom (Thalassiosira weissflogii) and a cyanobacterium (Synechococcus elongatus).

Exopolymer particles are found throughout the ocean and play a significant biogeochemical role in carbon cycling. Transparent exopolymer particles (TEP) are composed of acid polysaccharides, and Coomassie staining particles (CSP) are proteins. TEPs have been extensively studied in the ocean, while CSP have been largely overlooked. The objective of this research was to determine the role of stress and cell permeability in the formation of TEP and CSP. The diatom Thalassiosira weissflogii and cyanobacterium Synechococcus elongatus were grown in batch cultures and exposed to hydrogen peroxide (0, 10, and 100 µM) as an environmental stressor. There was no correlation between TEP and CSP concentrations, indicating that they are different populations of particles rather than different chemical components of the same particles. CSP concentrations were not affected by hydrogen peroxide concentration and did not correlate with indicators of stress and cell death. In contrast, TEP concentrations in both taxa were correlated with a decrease in the effective quantum yield of photosystem II, increased activity of caspase-like enzymes, and an increase in the proportion of the population with permeable cell membranes, indicating that TEP production was associated with the process of cell death. These data show that different environmental factors and physiological processes affected the production of TEP and CSP by phytoplankton. TEP and CSP are separate populations of exopolymer particles with potentially different biogeochemical roles in the ocean.

Assessing the umbrella value of a range-wide conservation network for jaguars (Panthera onca).

Umbrella species are employed as conservation short-cuts for the design of reserves or reserve networks. However, empirical data on the effectiveness of umbrellas is equivocal, which has prevented more widespread application of this conservation strategy. We perform a novel, large-scale evaluation of umbrella species by assessing the potential umbrella value of a jaguar (Panthera onca) conservation network (consisting of viable populations and corridors) that extends from Mexico to Argentina. Using species richness, habitat quality, and fragmentation indices of ~1500 co-occurring mammal species, we show that jaguar populations and corridors overlap a substantial amount and percentage of high-quality habitat for co-occurring mammals and that the jaguar network performs better than random networks in protecting high-quality, interior habitat. Significantly, the effectiveness of the jaguar network as an umbrella would not have been noticeable had we focused on species richness as our sole metric of umbrella utility. Substantial inter-order variability existed, indicating the need for complementary conservation strategies for certain groups of mammals. We offer several reasons for the positive result we document, including the large spatial scale of our analysis and our focus on multiple metrics of umbrella effectiveness. Taken together, our results demonstrate that a regional, single-species conservation strategy can serve as an effective umbrella for the larger community and should help conserve viable populations and connectivity for a suite of co-occurring mammals. Current and future range-wide planning exercises for other large predators may therefore have important umbrella benefits.

Dissolved organic matter composition drives the marine production of brominated very short-lived substances.

Brominated very short-lived substances (BrVSLS), such as bromoform, are important trace gases for stratospheric ozone chemistry. These naturally derived trace gases are formed via bromoperoxidase-mediated halogenation of dissolved organic matter (DOM) in seawater. Information on DOM type in relation to the observed BrVSLS concentrations in seawater, however, is scarce. We examined the sensitivity of BrVSLS production in relation to the presence of specific DOM moieties. A total of 28 model DOM compounds in artificial seawater were treated with vanadium bromoperoxidase (V-BrPO). Our results show a clear dependence of BrVSLS production on DOM type. In general, molecules that comprise a large fraction of the bulk DOM pool did not noticeably affect BrVSLS production. Only specific cell metabolites and humic acid appeared to significantly enhance BrVSLS production. Amino acids and lignin phenols suppressed enzyme-mediated BrVSLS production and may instead have formed halogenated nonvolatile molecules. Dibromomethane production was not observed in any experiments, suggesting it is not produced by the same pathway as the other BrVSLS. Our results suggest that regional differences in DOM composition may explain the observed BrVSLS concentration variability in the global ocean. Ultimately, BrVSLS production and concentrations are likely affected by DOM composition, reactivity, and cycling in the ocean.

Transparent exopolymer particle production and aggregation by a marine planktonic diatom (Thalassiosira weissflogii) at different growth rates.

Transparent exopolymer particles (TEP) play an important role in the ocean carbon cycle as they are sticky and affect particle aggregation and the biological carbon pump. We investigated the effect of growth rate on TEP production in nitrogen limited semi-continuous cultures of the diatom Thalassiosira weissflogii (Grunow) G. Fryxell & Hasle. Steady-state diatom concentrations and other indicators of biomass (chl a, and total carbohydrate) were inversely related to growth rate, while individual cell volume increased with growth rate. There was no change in total TEP area with growth rate; however, individual TEP were larger at high growth rates and the number of individual TEP particles was lower. TEP concentration per cell was higher at higher growth rates. SYTOX Green staining showed that <5% of the diatom population had permeable cell membranes, with the proportion increasing at low growth rates. However, TEP production rates were greater at high growth rates, refuting our hypothesis that TEP formation is dependent on dying cells with compromised cell membranes in a diatom population. Measurements of particle size distribution in the cultures using laser scattering showed that they were most aggregated at high growth rates. These results indicate a coupling between TEP production and growth rate in diatoms under N limitation, with fast growing T. weissflogii producing more TEP and aggregates.

Prey switching as a means of enhancing persistence in predators at the trailing southern edge.

Understanding the effects of climate change on species' persistence is a major research interest; however, most studies have focused on responses at the northern or expanding range edge. There is a pressing need to explain how species can persist at their southern range when changing biotic interactions will influence species occurrence. For predators, variation in distribution of primary prey owing to climate change will lead to mismatched distribution and local extinction, unless their diet is altered to more extensively include alternate prey. We assessed whether addition of prey information in climate projections restricted projected habitat of a specialist predator, Canada lynx (Lynx canadensis), and if switching from their primary prey (snowshoe hare; Lepus americanus) to an alternate prey (red squirrel; Tamiasciurus hudsonicus) mitigates range restriction along the southern range edge. Our models projected distributions of each species to 2050 and 2080 to then refine predictions for southern lynx on the basis of varying combinations of prey availability. We found that models that incorporated information on prey substantially reduced the total predicted southern range of lynx in both 2050 and 2080. However, models that emphasized red squirrel as the primary species had 7-24% lower southern range loss than the corresponding snowshoe hare model. These results illustrate that (i) persistence at the southern range may require species to exploit higher portions of alternate food; (ii) selection may act on marginal populations to accommodate phenotypic changes that will allow increased use of alternate resources; and (iii) climate projections based solely on abiotic data can underestimate the severity of future range restriction. In the case of Canada lynx, our results indicate that the southern range likely will be characterized by locally varying levels of mismatch with prey such that the extent of range recession or local adaptation may appear as a geographical mosaic.

The subtle role of climate change on population genetic structure in Canada lynx.

Anthropogenically driven climatic change is expected to reshape global patterns of species distribution and abundance. Given recent links between genetic variation and environmental patterns, climate change may similarly impact genetic population structure, but we lack information on the spatial and mechanistic underpinnings of genetic-climate associations. Here, we show that current genetic variability of Canada lynx (Lynx canadensis) is strongly correlated with a winter climate gradient (i.e. increasing snow depth and winter precipitation from west-to-east) across the Pacific-North American (PNO) to North Atlantic Oscillation (NAO) climatic systems. This relationship was stronger than isolation by distance and not explained by landscape variables or changes in abundance. Thus, these patterns suggest that individuals restricted dispersal across the climate boundary, likely in the absence of changes in habitat quality. We propose habitat imprinting on snow conditions as one possible explanation for this unusual phenomenon. Coupling historical climate data with future projections, we also found increasingly diverging snow conditions between the two climate systems. Based on genetic simulations using projected climate data (2041-2070), we predicted that this divergence could lead to a threefold increase in genetic differentiation, potentially leading to isolated east-west populations of lynx in North America. Our results imply that subtle genetic structure can be governed by current climate and that substantive genetic differentiation and related ecological divergence may arise from changing climate patterns.

Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation.

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Phosphorylation-Driven Epichaperome Assembly: A Critical Regulator of Cellular Adaptability and Proliferation.

The intricate protein-chaperone network is vital for cellular function. Recent discoveries have unveiled the existence of specialized chaperone complexes called epichaperomes, protein assemblies orchestrating the reconfiguration of protein-protein interaction networks, enhancing cellular adaptability and proliferation. This study delves into the structural and regulatory aspects of epichaperomes, with a particular emphasis on the significance of post-translational modifications in shaping their formation and function. A central finding of this investigation is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 situated within an intrinsically disordered region, as critical determinants in epichaperome assembly. Our data demonstrate that the phosphorylation of these serine residues enhances HSP90's interaction with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Furthermore, this study establishes a direct link between epichaperome function and cellular physiology, especially in contexts where robust proliferation and adaptive behavior are essential, such as cancer and stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone complexes in diseases characterized by epichaperome dysregulation, bridging the gap between fundamental research and precision medicine.

Evidence for large-scale effects of competition: niche displacement in Canada lynx and bobcat.

Determining the patterns, causes and consequences of character displacement is central to our understanding of competition in ecological communities. However, the majority of competition research has occurred over small spatial extents or focused on fine-scale differences in morphology or behaviour. The effects of competition on broad-scale distribution and niche characteristics of species remain poorly understood but critically important. Using range-wide species distribution models, we evaluated whether Canada lynx (Lynx canadensis) or bobcat (Lynx rufus) were displaced in regions of sympatry. Consistent with our prediction, we found that lynx niches were less similar to those of bobcat in areas of sympatry versus allopatry, with a stronger reliance on snow cover driving lynx niche divergence in the sympatric zone. By contrast, bobcat increased niche breadth in zones of sympatry, and bobcat niches were equally similar to those of lynx in zones of sympatry and allopatry. These findings suggest that competitively disadvantaged species avoid competition at large scales by restricting their niche to highly suitable conditions, while superior competitors expand the diversity of environments used. Our results indicate that competition can manifest within climatic niche space across species' ranges, highlighting the importance of biotic interactions occurring at large spatial scales on niche dynamics.

Partial COVID-19 closure of a national park reveals negative influence of low-impact recreation on wildlife spatiotemporal ecology.

Human presence exerts complex effects on the ecology of species, which has implications for biodiversity persistence in protected areas experiencing increasing human recreation levels. However, the difficulty of separating the effect on species of human presence from other environmental or disturbance gradients remains a challenge. The cessation of human activity that occurred with COVID-19 restrictions provides a 'natural experiment' to better understand the influence of human presence on wildlife. Here, we use a COVID-19 closure within a heavily visited and highly protected national park (Glacier National Park, MT, USA) to examine how 'low-impact' recreational hiking affects the spatiotemporal ecology of a diverse mammal community. Based on data collected from camera traps when the park was closed and then subsequently open to recreation, we found consistent negative responses to human recreation across most of our assemblage of 24 species, with fewer detections, reduced site use, and decreased daytime activity. Our results suggest that the dual mandates of national parks and protected areas to conserve biodiversity and promote recreation have potential to be in conflict, even for presumably innocuous recreational activities. There is an urgent need to understand the fitness consequences of these spatiotemporal changes to inform management decisions in protected areas.

Food quality, security, and thermal refuge influence the use of microsites and patches by pygmy rabbits (Brachylagus idahoensis) across landscapes and seasons.

How intensely animals use habitat features depends on their functional properties (i.e., how the feature influences fitness) and the spatial and temporal scale considered. For herbivores, habitat use is expected to reflect the competing risks of starvation, predation, and thermal stress, but the relative influence of each functional property is expected to vary in space and time. We examined how a dietary and habitat specialist, the pygmy rabbit (Brachylagus idahoensis), used these functional properties of its sagebrush habitat-food quality, security, and thermal refuge-at two hierarchical spatial scales (microsite and patch) across two seasons (winter and summer). At the microsite and patch scales, we determined which plant functional traits predicted the number of bites (i.e., foraging) by pygmy rabbits and the number of their fecal pellets (i.e., general habitat use). Pygmy rabbits used microsites and patches more intensely that had higher crude protein and aerial concealment cover and were closer to burrows. Food quality was more influential when rabbits used microsites within patches. Security was more influential in winter than summer, and more at Cedar Gulch than Camas. However, the influence of functional properties depended on phytochemical and structural properties of sagebrush and was not spatiotemporally consistent. These results show function-dependent habitat use that varied according to specific activities by a central-place browsing herbivore. Making spatially explicit predictions of the relative value of habitat features that influence different types of habitat use (i.e., foraging, hiding, and thermoregulating) will improve how we predict patterns of habitat use by herbivores and how we monitor and manage functional traits within habitats for wildlife.

Skin Aging in Long-Lived Naked Mole-Rats Is Accompanied by Increased Expression of Longevity-Associated and Tumor Suppressor Genes.

Naked mole-rats (NMRs) (Heterocephalus glaber) are long-lived mammals that possess a natural resistance to cancer and other age-related pathologies, maintaining a healthy life span >30 years. In this study, using immunohistochemical and RNA-sequencing analyses, we compare skin morphology, cellular composition, and global transcriptome signatures between young and aged (aged 3‒4 vs. 19‒23 years, respectively) NMRs. We show that similar to aging in human skin, aging in NMRs is accompanied by a decrease in epidermal thickness; keratinocyte proliferation; and a decline in the number of Merkel cells, T cells, antigen-presenting cells, and melanocytes. Similar to that in human skin aging, expression levels of dermal collagens are decreased, whereas matrix metalloproteinase 9 and matrix metalloproteinase 11 levels increased in aged versus in young NMR skin. RNA-sequencing analyses reveal that in contrast to human or mouse skin aging, the transcript levels of several longevity-associated (Igfbp3, Igf2bp3, Ing2) and tumor-suppressor (Btg2, Cdkn1a, Cdkn2c, Dnmt3a, Hic1, Socs3, Sfrp1, Sfrp5, Thbs1, Tsc1, Zfp36) genes are increased in aged NMR skin. Overall, these data suggest that specific features in the NMR skin aging transcriptome might contribute to the resistance of NMRs to spontaneous skin carcinogenesis and provide a platform for further investigations of NMRs as a model organism for studying the biology and disease resistance of human skin.