Project description:During aging, stromal functions are thought to be impaired, yet little is known whether this stems from molecular and cellular changes of fibroblasts, a major component of stroma. Using population- and single-cell whole transcriptomics, and long-term lineage tracing, we studied alterations in murine dermal fibroblasts during physiological aging under different dietary regimes known to affect longevity. We show that the identity of aged fibroblasts becomes undefined, with the distinct fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but intriguingly, also gain adipogenic traits, paradoxically becoming similar to neonatal pro-adipogenic fibroblasts. These age-related alterations are sensitive to systemic changes in metabolism: long-term caloric restriction prevents them in old fibroblasts in a reversible manner, whereas a high-fat diet potentiates them in young fibroblasts. Finally, inhibition of the master regulator of adipogenesis, PPARgamma, attenuates fibroblast aging in vivo, providing potential anti-aging therapeutic alternatives to caloric restriction.
Project description:During aging, stromal functions are thought to be impaired, yet little is known whether this stems from molecular and cellular changes of fibroblasts, a major component of stroma. Using population- and single-cell whole transcriptomics, and long-term lineage tracing, we studied alterations in murine dermal fibroblasts during physiological aging under different dietary regimes known to affect longevity. We show that the identity of aged fibroblasts becomes undefined, with the distinct fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but intriguingly, also gain adipogenic traits, paradoxically becoming similar to neonatal pro-adipogenic fibroblasts. These age-related alterations are sensitive to systemic changes in metabolism: long-term caloric restriction prevents them in old fibroblasts in a reversible manner, whereas a high-fat diet potentiates them in young fibroblasts. Finally, inhibition of the master regulator of adipogenesis, PPARgamma, attenuates fibroblast aging in vivo, providing potential anti-aging therapeutic alternatives to caloric restriction.
Project description:During aging, stromal functions are thought to be impaired, yet little is known whether this stems from molecular and cellular changes of fibroblasts, a major component of stroma. Using population- and single-cell whole transcriptomics, and long-term lineage tracing, we studied alterations in murine dermal fibroblasts during physiological aging under different dietary regimes known to affect longevity. We show that the identity of aged fibroblasts becomes undefined, with the distinct fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but intriguingly, also gain adipogenic traits, paradoxically becoming similar to neonatal pro-adipogenic fibroblasts. These age-related alterations are sensitive to systemic changes in metabolism: long-term caloric restriction prevents them in old fibroblasts in a reversible manner, whereas a high-fat diet potentiates them in young fibroblasts. Finally, inhibition of the master regulator of adipogenesis, PPARgamma, attenuates fibroblast aging in vivo, providing potential anti-aging therapeutic alternatives to caloric restriction.
Project description:Background: Skin homeostasis is mediated by dermal fibroblasts and is affected by aging. Although age-related heterogeneity in fibroblasts has been reported, the effects of donor and species on this heterogeneity are unclear. Methods: To analyze age-related transcriptomic changes in human dermal fibroblasts, single-cell RNA sequencing was performed on dermal fibroblasts (ASF-4 cells) collected from the inner forearm of a volunteer over three decades. Results: Four main cell subpopulations changed with donor age and showed proliferative, homeostasis, fibrotic, and senescence functional annotations. The downregulation of the expression of genes encoding key extracellular matrix production and mechanotransduction components decreased with donor age. Interestingly, dermal fibroblasts have two putative differentiation pathways: one that involves the acquisition of senescent properties and the acquisition of fibrotic properties without the suppression of proliferation. Aging induced fibroblast differentiation in a manner involving the acquisition of senescent properties. Conclusion:Reconciling the various aspects of fibroblast heterogeneity may provide insight into the mechanisms underlying human skin aging and associated phenomena, including wrinkles, sagging, delayed wound healing, and suppressed scar formation.
Project description:In this study, we have analyzed DNA methylation changes upon aging of human dermal fibroblasts by using the HumanMethylation27 BeadChip assessing 27,578 unique CpG sites. Cells were isolated from skin samples donated by young (6-23 years) and elderly (60-73 years) patients undergoing surgical interventions. Strikingly, global DNA-methylation profiles of fibroblasts from the same anatomical site clustered closely together indicating that fibroblasts maintain positional memory even after in vitro culture.
Project description:During aging, stromal functions are thought to be impaired, yet little is known whether this stems from molecular and cellular changes of fibroblasts, a major component of stroma. Using population- and single-cell whole transcriptomics, and long-term lineage tracing, we studied alterations in murine dermal fibroblasts during physiological aging under different dietary regimes known to affect longevity. We show that the identity of aged fibroblasts becomes undefined, with the distinct fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but intriguingly, also gain adipogenic traits, paradoxically becoming similar to neonatal pro-adipogenic fibroblasts. These age-related alterations are sensitive to systemic changes in metabolism: long-term caloric restriction prevents them in old fibroblasts in a reversible manner, whereas a high-fat diet potentiates them in young fibroblasts. Finally, inhibition of the master regulator of adipogenesis, PPARgamma, attenuates fibroblast aging in vivo, providing potential anti-aging therapeutic alternatives to caloric restriction.
Project description:During aging, stromal functions are thought to be impaired, yet little is known whether this stems from molecular and cellular changes of fibroblasts, a major component of stroma. Using population- and single-cell whole transcriptomics, and long-term lineage tracing, we studied alterations in murine dermal fibroblasts during physiological aging under different dietary regimes known to affect longevity. We show that the identity of aged fibroblasts becomes undefined, with the distinct fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but intriguingly, also gain adipogenic traits, paradoxically becoming similar to neonatal pro-adipogenic fibroblasts. These age-related alterations are sensitive to systemic changes in metabolism: long-term caloric restriction prevents them in old fibroblasts in a reversible manner, whereas a high-fat diet potentiates them in young fibroblasts. Finally, inhibition of the master regulator of adipogenesis, PPARgamma, attenuates fibroblast aging in vivo, providing potential anti-aging therapeutic alternatives to caloric restriction.