DNA damage markers in dermal fibroblasts in vitro reflect chronological donor age

Waaijer, M.E.C.; Croco, Eleonora; Westendorp, Rudi G.J.; Slagboom, P. Eline; Sedivy, John M.; Lorenzini, Antonello; Maier, Andrea B.

doi:10.18632/aging.100890

Cited by 18 publications

(16 citation statements)

References 38 publications

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“…There was no significant difference in terms of cellular senescence status between NHDFs derived from young and old donors. These results are consistent with previous observations that the replicative senescence of fibroblasts in culture shows no correlation with donor age …”

Section: Resultssupporting

confidence: 93%

Oxytocin alleviates cellular senescence through oxytocin receptor‐mediated extracellular signal‐regulated kinase/Nrf2 signalling

Cho

Kim

et al. 2019

Br J Dermatol

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Summary Background Oxytocin (OT) is a neuropeptide hormone that has many beneficial biological effects, including protection against age‐related disorders. However, less is known about its role in intrinsic skin ageing, which is accelerated by an increase in senescent cell fraction in skin tissue. Objectives To investigate the novel function and the underlying mechanism of OT in preventing cellular senescence in normal human dermal fibroblasts (NHDFs) isolated from the skin of female donors of different ages. Methods NHDFs from young and old donors were exposed to conditioned medium from senescent or control NHDFs in the presence or absence of 10 nmol L−1 OT for 3 days, and were continuously subcultured for 12 days. Subsequently, various age‐associated signs of senescence including decreased proliferation rate, elevated p16 and p21 levels, and positivity for senescence‐associated β‐galactosidase expression were examined. Results We found that OT suppressed senescence‐associated secretory phenotype‐induced senescence in NHDFs, and its effect depended on the age of the donor's NHDFs. The inhibitory effects of OT required signalling by OT receptor‐mediated extracellular signal‐regulated kinase/Nrf2 (nuclear factor erythroid 2‐related factor 2). The age‐dependent antisenescence effects of OT are closely related to hypermethylation of the OT receptor gene (OXTR). Conclusions Our findings bring to light the role of OT in the prevention of skin ageing, which might allow development of new clinical strategies. What's already known about this topic? Senescent keratinocytes and fibroblasts accumulate with age in the skin and contribute to the loss of skin function and integrity during ageing. Senescent cells secrete senescence‐associated secretory phenotype (SASP), which includes the release of proinflammatory cytokines such as interleukin (IL)‐6 and IL‐1, chemokines, extracellular matrix‐remodelling proteases and growth factors. The neuropeptide oxytocin (OT) and its receptor (OXTR) have protective effects against various age‐related disorders. What does this study add? OT suppressed SASP‐induced cellular senescence in normal human dermal fibroblasts (NHDFs), depending on the age of the NHDFs’ donor. The inhibitory effects of OT on cellular senescence required OXTR‐mediated phosphorylation of extracellular signal‐regulated kinase, which enhanced nuclear localization of Nrf2, a vital factor in the antioxidant defence system. The age‐specific antisenescent effects of OT were closely related to hypermethylation of OXTR. What is the translational message? Our results suggest that OT and OXTR agonists could be clinically promising agents for the improvement of age‐associated skin ageing, especially in women.

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Section: Resultssupporting

confidence: 93%

Oxytocin alleviates cellular senescence through oxytocin receptor‐mediated extracellular signal‐regulated kinase/Nrf2 signalling

Cho

Kim

et al. 2019

Br J Dermatol

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“…Dysfunctional telomeres resemble DSBs and they have been observed during ageing, cancer and a number of medical conditions11121314151617. Apart from telomeric repeat-containing RNA (TERRA), a non-coding UUAGGG-rich transcript starting from promoters located in the subtelomeric region1819, in mammals no other transcripts at telomeres have been characterized so far.…”

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confidence: 99%

DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

et al. 2017

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The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.

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“…Although the age span of the patients was not great and is sometimes used as a single age category in aging studies [18, 19], a remarkable inter-individual variability in the clonogenic capacity of their skin fibroblasts was found as evident from the results of their clonogenic analysis (Table 1). Indeed, the variability was demonstrated both in ECO-f (from 9.7 up to 61.0%) and in the fractions of each colony phenotype.…”

Section: Resultsmentioning

confidence: 99%

Diffuse colonies of human skin fibroblasts in relation to cellular senescence and proliferation

Zorin

Зорина

Сметанина

et al. 2017

Aging

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Development of personalized skin treatment in medicine and skin care may benefit from simple and accurate evaluation of the fraction of senescent skin fibroblasts that lost their proliferative capacity. We examined whether enriched analysis of colonies formed by primary human skin fibroblasts, a simple and widely available cellular assay, could reveal correlations with the fraction of senescent cells in heterogenic cell population. We measured fractions of senescence associated β-galactosidase (SA-βgal) positive cells in either mass cultures or colonies of various morphological types (dense, mixed and diffuse) formed by skin fibroblasts from 10 human donors. Although the donors were chosen to be within the same age group (33-54 years), the colony forming efficiency of their fibroblasts (ECO-f) and the percentage of dense, mixed and diffuse colonies varied greatly among the donors. We showed, for the first time, that the SA-βgal positive fraction was the largest in diffuse colonies, confirming that they originated from cells with the least proliferative capacity. The percentage of diffuse colonies was also found to correlate with the SA-βgal positive cells in mass culture. Using Ki67 as a cell proliferation marker, we further demonstrated a strong inverse correlation (r=−0.85, p=0.02) between the percentage of diffuse colonies and the fraction of Ki67+ cells. Moreover, a significant inverse correlation (r=−0.94, p=0.0001) between the percentage of diffuse colonies and ECO-f was found. Our data indicate that quantification of a fraction of diffuse colonies may provide a simple and useful method to evaluate the extent of cellular senescence in human skin fibroblasts.

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DNA damage markers in dermal fibroblasts in vitro reflect chronological donor age

Cited by 18 publications

References 38 publications

Oxytocin alleviates cellular senescence through oxytocin receptor‐mediated extracellular signal‐regulated kinase/Nrf2 signalling

Oxytocin alleviates cellular senescence through oxytocin receptor‐mediated extracellular signal‐regulated kinase/Nrf2 signalling

DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

Diffuse colonies of human skin fibroblasts in relation to cellular senescence and proliferation

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