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Beyond Grafting - Uncovering the Molecular Mechanisms of Human Tissue Aging Using Primary Adipose Tissue as a Model
Ivona Percec, M.D. Ph.D..
University of Pennsylvania, Philadelphia, PA, USA.
Background: The global aging process is a complex biological phenomenon that involves thousands of genes orchestrated in conserved molecular pathways. We have recently learned that longevity is heritable across species, that caloric restriction increases longevity and that epigenetic modifications may be more important than genetic ones. Unfortunately, these findings are almost exclusively derived from either in vitro assays or model organisms calling into question their applicability to normal human aging. Remarkably, it is our clinical experience with fat grafting that has provided us with perhaps the most critical insight into non-pathologic human tissue aging. We now know that the viability of grafted adipose tissue decreases with age, that adipose-derived stem cells (ASCs) decrease in number and activity with age, and that distinct anatomic compartments age differently. These observations have led us to hypothesize that primary human adipose tissue is an excellent model with which to study normal human aging and derive clinical implications for adipose tissue manipulation.
Methods: Subcutaneous adipose tissue samples from the periorbital area, face, breast and abdomen are collected from male and female patients (ages 18-85), who are undergoing aesthetic surgery by plastic surgeons at the University of Pennsylvania. Adipocytes, stromal vascular fraction (SVF) and adipose-derived stem cells (ASCs) are isolated from each specimen and examined in parallel. Genome-wide transcriptional differences between cell type, anatomic compartment and age are characterized using Affymetrix gene chip technology. A focused analysis of RNA and protein expression of the Sirtuin gene family (SIRT1-7) investigates the contribution of this molecular pathway whose role has been well documented in model organism aging to normal human tissue aging.
Results: Using our model of adipose tissue aging of purified populations of adipocytes, SVFs, and ASCs from subcutaneous adipose tissues of different ages, we demonstrate that primary human adipose tissue can successfully be analyzed via genome-wide approaches. We have identified transcriptional differences in over 700 differentially expressed genes and establish that transcriptional modifications more important in distinguishing between cell types than between age-related changes. Furthermore, we demonstrate for the first time that the human Sirtuin histone deacetylation genes (SIRT1-7), which are known to be involved in aging and adipose metabolism, regulate adipose tissue aging in a differential manner via specific effects on cell type and chronological age. These effects are observed at both the protein and RNA level.
Conclusions: We have demonstrated that human adipose tissue is an excellent model for the investigation of human tissue aging. Adipocytes and the stromal vascular fractions differ in their molecular aging phenotypes. Consequently, in order to truly dissect out the contribution of genes and pathways to adipose aging, tissue analyses must be carried out in a cell-specific manner. Our data suggest that age-related differences are more likely to result from posttranscriptional or epigenetic modifications than by regulation at the RNA level. As such, we establish a new role for the epigenetic modifiers Sirtuin genes in adipose tissue aging. These findings and planned future experiments are critical for advancing the understanding of how human tissues age.
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