The hallmarks of fibroblast ageing

Tigges, Julia; Krutmann, Jean; Fritsche, Ellen; Haendeler, Judith; Schaal, Heiner; Fischer, Jens W.; Kalfalah, Faiza; Reinke, Hans; Reifenberger, Guido; Stühler, Kai; Ventura, Natascia; Gundermann, Sabrina; Boukamp, Petra; Boege, Fritz

doi:10.1016/j.mad.2014.03.004

Cited by 185 publications

(165 citation statements)

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“…1,2 Of all the features associated with aging, a gradual destabilization of genome integrity is perhaps the most fundamental as increased genomic instability may lead to other age-associated phenotypes such as cellular senescence and stem cell exhaustion. Indeed, for the past several decades, numerous studies have indicated that DNA mutations and chromosomal rearrangements gradually accumulate with age.…”

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Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Zhang

Chen

et al. 2016

Cell Death Differ

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Failing to repair DNA double-strand breaks by either nonhomologous end joining (NHEJ) or homologous recombination (HR) poses a threat to genome integrity, and may have roles in the onset of aging and age-related diseases. Recent work indicates an age-related decrease of NHEJ efficiency in mouse models, but whether NHEJ and HR change with age in humans and the underlying mechanisms of such a change remain uncharacterized. Here, using 50 eyelid fibroblast cell lines isolated from healthy donors at the age of 16-75 years, we demonstrate that the efficiency and fidelity of NHEJ, and the efficiency of HR decline with age, leading to increased IR sensitivity in cells isolated from old donors. Mechanistic analysis suggests that decreased expression of XRCC4, Lig4 and Lig3 drives the observed, age-associated decline of NHEJ efficiency and fidelity. Restoration of XRCC4 and Lig4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts. In contrast, essential HR-related factors, such as Rad51, do not change in expression level with age, but Rad51 exhibits a slow kinetics of recruitment to DNA damage sites in aged fibroblasts. Further rescue experiments indicate that restoration of XRCC4 and Lig4 may suppress the onset of stress-induced premature cellular senescence, suggesting that improving NHEJ efficiency and fidelity by targeting the NHEJ pathway holds great potential to delay aging and mitigate aging-related pathologies. Cell Death and Differentiation (2016) 23, 1765-1777; doi:10.1038/cdd.2016.65; published online 8 July 2016Aging in mammals is a complex biological process, characterized by several major hallmarks.1,2 Of all the features associated with aging, a gradual destabilization of genome integrity is perhaps the most fundamental as increased genomic instability may lead to other age-associated phenotypes such as cellular senescence and stem cell exhaustion. Indeed, for the past several decades, numerous studies have indicated that DNA mutations and chromosomal rearrangements gradually accumulate with age.3-6 Of all types of DNA lesions, which may contribute to the gradual loss of genetic information during aging, DNA double-strand breaks (DSBs) are the most hazardous to cells as unrepaired or inappropriately repaired DSBs can cause insertions, deletions and chromosomal rearrangements. Using different analysis approaches, several studies have demonstrated that aging is often associated with the accumulation of DNA DSBs in various organs and tissues in mammals such as mice and humans. [7][8][9][10][11] Moreover, a recent study provides direct evidence that an induction of DNA DSBs in genomes causes aging in mouse livers.12 However, why DNA DSBs accumulate with age remains an open question. A number of studies indicate that it may be a consequence of a progressing imbalance between DNA damage and the efficiency of the molecular machinery that catalyzes DNA repair. 7,9,11 Two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) evolved to repair DNA DSBs. NHEJ is...

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mentioning

confidence: 99%

Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Zhang

Chen

et al. 2016

Cell Death Differ

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“…O envelhecimento está associado a mudanças que ocorrem em nível celular e que levam à perda progressiva da função dos tecidos, além da diminuição da resistência ao estresse, da eficiência metabólica e do potencial de adaptação. Estas mudanças prejudicam a função basal e a resposta a estímulos ambientais, resultando na diminuição da capacidade de reparar danos, predisposição do organismo a doenças e disfunção permanente (Yaar e Gilchrest, 1998;Tigges et al, 2014).…”

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“…Fatores intrínsecos e extrínsecos atuam na modificação de propriedades da pele no processo de envelhecimento cutâneo, podendo este ser, assim, classificado como envelhecimento intrínseco ou extrínseco (Gilchrest, 1989;Uitto e Bernstein, 1998 (Jenkins, 2002;Mine et al, 2008;Zouboulis e Makrantonaki, 2011;Raut et al, 2012 (Baumann, 2007;Tigges et al, 2014;Zeng et al, 2014).…”

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“…Na pele de jovens (20 a 30 anos), as fibras de colágeno intactas são abundantes e organizadas. Em contraste, na pele envelhecida (> 80 anos), as fibras de colágeno são fragmentadas e desorganizadas (Uitto e Bernstein, 1998;Quan et al, 2013;Tigges et al, 2014).…”

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“…Aliado ao aumento da atividade das MMP está a diminuição da produção de seus inibidores, os inibidores teciduais de metaloproteinases (TIMP), o 7 que contribui para a desregulação crônica da síntese e degradação de componentes da matriz extracelular, que se constitui como a maior característica do envelhecimento cutâneo (Fisher et al, 2009;Sárdy, 2009 (Harman, 1955;Pamplona, 2008 (Aruoma, 1998;Fisher et al, 2002;Tigges et al, 2014).…”

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Avaliação da expressão gênica de colágeno em fibroblastos tratados com extratos de fungos endofíticos

Araújo¹

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Skin aging process is very complex and can be classified as intrinsic aging, primarily determined by genetic factors, and extrinsic aging, induced by nutritional and behavioral factors, such as chronic exposure to ultraviolet radiation, excessive alcohol consumption, smoking and nutritional disorders. Skin aging is characterized by morphological and functional changes, which can cause wrinkling, scaling, dryness, pigmentation abnormalities and skin cancer. Some of the disorders that affect the skin aging are mainly due to oxidative stress promoted by reactive oxygen species that are able to change the balance between synthesis and degradation of the dermal extracellular matrix components, favoring degradation rather than the synthesis process. Natural products protect skin from damage induced by oxidative stress and may act in important pathways in the skin aging. Among the possible sources for obtaining natural products it is possible to highlight the endophytic fungi, which are able to produce a great diversity of natural compounds. The objective of this study was to evaluate the influence of treatment with metabolites produced by two endophytic fungi isolated from Bauhinia variegate leaves on genic expression of collagen type I, metalloproteinase type 1 and tissue inhibitor of metalloproteinase type 1 in human dermal fibroblasts exposed to oxidative stress. The results show that both fungi were able to produce polyphenolic compounds and, more specifically, flavonoids. Treatment of fibroblasts with the extract produced by one of the endophytic fungi increased the expression of collagen type I gene, reduced the expression of metalloproteinase type 1 gene and inhibited metalloproteinase type 2 activity, suggesting that metabolites produced by this fungus can be benefic in prevent skin aging.

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Targeted Therapeutics Delivery by Exploiting Biophysical Properties of Senescent Cells

Low

Chan

Tay

2021

Adv Funct Materials

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Cellular senescence refers to a state of irreversible arrest of cell proliferation in response to various forms of cellular stress. It is known that the accumulation of senescent cells is a hallmark of aging, and mounting evidence has shown that the chronic accumulation of senescent cells is a significant contributor to various deleterious age-related pathologies. To limit the detrimental impacts of cellular senescence, there has been growing interest in targeted delivery of therapeutics to senescent cells to treat age-related pathologies and promote healthy aging. Two popular strategies include the elimination of senescent cells using senolytic drugs, and rejuvenation of senescent cells. To that end, it is integral that the delivery of senolytics, senomorphics or rejuvenating biomolecules to senescent cells are highly selective to enhance delivery efficacy and safety. However, there is little understanding of how senescence-associated biophysical changes such as cellular size and stiffness can be exploited for targeted therapeutics delivery. In this review, the biomolecular and biophysical markers of senescence along with senescence models and emerging therapeutics are first described. This review then focuses on how biophysical properties can be exploited for targeted therapeutics delivery, using approaches like nanoparticles, electroporation, sonoporation, photoporation and high aspect-ratio nanostructures to senescent cells.

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The hallmarks of fibroblast ageing

Cited by 185 publications

References 297 publications

Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Avaliação da expressão gênica de colágeno em fibroblastos tratados com extratos de fungos endofíticos

Targeted Therapeutics Delivery by Exploiting Biophysical Properties of Senescent Cells

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