Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature William R. Swindell1*, Andrew Johnston2, Liou Sun3, Xianying Xing 2 , Gary J. Fisher2, Martha L. Bulyk4,5,6, James T. Elder2, Johann E. Gudjonsson2 1 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 3 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 4 Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 5 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 6 Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Background: Skin aging is associated with intrinsic processes that compromise the structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results: We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B- cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions: Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific. Citation: Swindell WR, Johnston A, Sun L, Xing X, Fisher GJ, et al. (2012) Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature. PLoS ONE 7(3): e33204. doi:10.1371/journal.pone.0033204 Editor: Francesco Falciani, University of Birmingham, United Kingdom Received May 18, 2011; Accepted February 13, 2012; Published March 7, 2012 Copyright: 2012 Swindell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the University of Michigan Nathan Shock Center Functional Activity Core (NIH AG013283). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: wswindell@genetics.med.harvard.edu Introduction Intrinsic skin aging is characterized by the progressive accumu- lation of senescent cells, thinning of the epidermis, decline in cell-to- cell adherence, reduction of collagen content, formation of fine wrinkles, and gradual loss of elastic material [1,2]. These features of normal skin aging can compromise health and well-being at older ages. Skin from older individuals, for instance, can lack the regenerative capacity required for wound healing and may provide a weakened immune barrier against pathogens, while also exhibiting an increased burden of somatic mutations that heightens susceptibility to melanomas and squamous cell carcinoma [1–5]. Senescent decline in skin function is simultaneous with broader systemic effects of normal aging, which involve diminished capacity to maintain homeostasis and overall loss of physiological reserve. The inter- and intra-cellular events associated with intrinsic skin aging parallel this broader aging process in certain respects, providing a model system to study mechanisms of aging [6]. In older individuals, for instance, the area occupied by elastic fibers in stained tissue sections is correlated between the reticular dermis and temporal artery, representing an extra-cellular feature of aging that is shared between the integumentary and vascular systems [7]. Health and appearance of human skin with age is closely linked to the synthesis of collagen and mechanisms that maintain the integrity of this abundant protein throughout the lifespan. With increasing age, abundance of both transforming growth factor b (TGF-b) and connective tissue growth factor (CTGF) declines in dermal fibroblasts, which contributes to reduced collagen synthesis and secretion [8]. Additionally, type I collagen fibrils become increasingly fragmented due to a self-perpetuating cycle in which increased oxidant levels PLoS ONE | www.plosone.org 1 March 2012 | Volume 7 | Issue 3 | e33204