Epidermal stem cells undergo age-associated changes

Doles, Jason; Keyes, William M.

doi:10.18632/aging.100530

Cited by 12 publications

(20 citation statements)

References 9 publications

(12 reference statements)

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“…Our observations of age-associated increase in MaSC frequency and decrease in stem cell function in mammary glands from C57BL6/J and BALB/c mice are similar to findings on hematopoietic, gastrointestinal, muscle, and skin stem cells [26]. However, these results differed from findings in FVB/N mice, where no age-specific difference of mammary stem cell activity was found between old (16 to 22 months) and young mice (age, 14 weeks) [27].…”

Section: Discussionsupporting

confidence: 88%

Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Dong

Gao

Shi

et al. 2016

Aging

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Breast cancer incidence increases during aging, yet the mechanism of age-associated mammary tumorigenesis is unclear. Mammary stem cells are believed to play an important role in breast tumorigenesis, but how their function changes with age is unknown. We compared mammary epithelial cells isolated from young and old mammary glands of different cohorts of C57BL6/J and BALB/c mice, and our findings revealed that old mammary glands were characterized by increased basal cell pool comprised of mostly CD49fhi cells, altered luminal-to-basal cell ratio, and irregular ductal morphology. More interestingly, basal stem cells in old mice were increased in frequency, but showed a functional decline of differentiation and increased neoplastic transformation potential. Gene signature enrichment analysis revealed a significant enrichment of a luminal cell gene expression signature in the basal stem cell-enriched population from old mice, suggesting some luminal cells were expressing basal markers. Immunofluorescence staining confirmed the presence of luminal cells with high CD49f expression in hyperplastic lesions implicating these cells as undergoing luminal to basal phenotypic changes during aging. Whole transcriptome analysis showed elevated immune and inflammatory responses in old basal stem cells and stromal cells, which may be the underlying cause for increased CD49fhi basal-like cells in aged glands.

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Section: Discussionsupporting

confidence: 88%

Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Dong

Gao

Shi

et al. 2016

Aging

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“…However, studies repeatedly have shown that tissue specific stem cells lose their functional potential with age (9), and this is associated with a decrease in absolute stem cell numbers in tissues such as muscle(10) brain(11), and melanocytes (12, 13), suggesting that reductions in the total stem cell number restricts the regenerative potential of that tissue. Several studies have shown that there is also intrinsic loss of stem cell reconstitution potential on a per cell basis in aged stem cells, thereby contributing to loss of homeostasis and regenerative potential (14, 15). Within the hematopoietic stem cell (HSC) compartment, aging is associated with significant loss of reconstitution potential at an individual cell level as assessed in transplantation assays, but an expansion in cell number (14, 16–20).…”

Section: Theories Of Aging Encompassing Damage Accumulationmentioning

confidence: 99%

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Beerman

2017

Seminars in Hematology

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Aging is associated with loss of functional potential of multiple tissue systems, and there has been significant interest in understanding how tissue specific cells contribute to this decline. DNA damage accumulation has been widely associated with aging in differentiated cell types. However, tissue specific stem cells were once thought to be a geno-protected population, as damage accrued in a stem cell population has the potential to be inherited by differentiated progeny as well as propagated within the stem cell compartment through self-renewal divisions. This review will discuss the evidence for DNA damage accumulation in the aged HSC compartment, potential drivers, and finally the consequences of the acquired damage.

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“…For example, perhaps the fluorophores reflect a requirement for amino acids near the deacetylation site with aromatic side chains. Indeed, several recent findings have revealed structural and positional requirements: Amino acids must be adjacent to the acetylated lysine for substrate recognition (60) and for activation to occur (81, 82, 115, 116). First, repositioning the AMC group in the substrate peptide from its canonical site immediately C-terminal to the acetylated lysine (+1) to +3, +6, +9, or +12 completely abrogated activation by STACs (81).…”

Section: Toward a Resolution And A Unified Activation Mechanism Targementioning

confidence: 99%

“…In a parallel study, more than 6,000 acetylated nontagged 13-mer peptide substrates were screened for their ability to support SIRT1 activation by resveratrol (116). As seen in the results for the synthetic STACs, there was a preference for large, hydrophobic residues in the C terminus, whereas positively charged residues antagonized activation.…”

Section: Toward a Resolution And A Unified Activation Mechanism Targementioning

confidence: 99%

Small-Molecule Allosteric Activators of Sirtuins

Sinclair

Guarente

2014

Annu. Rev. Pharmacol. Toxicol.

181

154

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The mammalian sirtuins (SIRT1–7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer’s disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.

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Epidermal stem cells undergo age-associated changes

Cited by 12 publications

References 9 publications

Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Small-Molecule Allosteric Activators of Sirtuins

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