Tissue-specific aging: a tale of functional asymmetry

Karakasilioti, Ismene; Garinis, George A.

doi:10.18632/aging.100635

Cited by 6 publications

(6 citation statements)

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“…Cellular aging is a driven force of tissue-specific aging (i.e., vascular aging) and aging of the entire organism [ 3 ], and only using in vitro models allow testing specific role of complex cellular pathways (such as cell senescence, autophagy, and mitochondrial function) in aging. In addition, availability of genetically modified mice justifies using murine primary cells to identify specific molecular targets linking cellular aging with tissue aging and aging of the entire organism.…”

Section: Discussionmentioning

confidence: 99%

“…Cellular aging is a complex biological process, which includes irreversible arrest of cell proliferation (cell senescence) and development of mitochondrial dysfunction [ 1 , 2 ]. Aging-induced alterations at the cellular level are main driving forces leading to tissue-specific aging and aging of the entire organism [ 3 ]. Mitochondria play vital roles in regulation of bioenergetics and metabolic responses.…”

Section: Introductionmentioning

confidence: 99%

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Insulin-Like Growth Factor I Prevents Cellular Aging via Activation of Mitophagy

Hou

Higashi

et al. 2020

Journal of Aging Research

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Mitochondrial dysfunction is a hallmark of cellular aging. Mitophagy is a critical mitochondrial quality control mechanism that removes dysfunctional mitochondria and contributes to cell survival. Insulin-like growth factor 1 (IGF-1) promotes survival of smooth muscle cells (SMCs), but its potential effect on cellular aging is unknown yet. We found that IGF-1 decreased cell senescence, prevented DNA telomere shortening, increased mitochondrial membrane potential, activated cytochrome C oxidase, and reduced mitochondrial DNA damage in long-term cultured (aged) aortic SMC, suggesting an antiaging effect. IGF-1 increased mitophagy in aged cells, and this was associated with decreased expression of cyclin-dependent kinase inhibitors p16 and p21 and elevated levels of Nrf2 and Sirt3, regulators of mitophagy and mitochondrial biogenesis. SiRNA-induced inhibition of either Nrf2 or Sirt3 blocked IGF-1-induced upregulation of mitophagy, suggesting that the Nrf2/Sirt3 pathway was required for IGF-1’s effect on mitophagy. PINK1 is a master regulator of mitophagy. PINK1 silencing suppressed mitophagy and inhibited IGF-1-induced antiaging effects in aged SMC, consistent with an essential role of mitophagy in IGF-1’s effect on cellular aging. Thus, IGF-1 inhibited cellular aging via Nrf2/Sirt3-dependent activation of mitophagy. Our data suggest that activation of IGF-1 signaling is a novel potential strategy to activate mitophagy and slow cellular aging.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin-Like Growth Factor I Prevents Cellular Aging via Activation of Mitophagy

Hou

Higashi

et al. 2020

Journal of Aging Research

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“…Owing to their congenital defects in genome maintenance, DNA repair-deficient animals are valid models to test for the physiological relevance of DNA damage-driven inflammation in premature disease onset during normal and accelerated aging ( Supplementary Table S1 ) ( van de Ven et al, 2007 ; Schumacher et al, 2008a ; Schumacher et al, 2008b ; Garinis, 2008 ; Garinis et al, 2008 ; Garinis et al, 2009 ; Schumacher et al, 2009 ; Karakasilioti et al, 2013 ; Karakasilioti and Garinis, 2014 ; Ioannidou et al, 2016 ; Chatzidoukaki et al, 2020 ). Mice with engineered mutations in NER genes reliably mimic most of the pleiotropic and heterogeneous pathological symptoms seen in NER syndromes ( Hasty et al, 2003 ; Niedernhofer et al, 2006 ; van der Pluijm et al, 2007 ; Schumacher et al, 2008a ; Schumacher et al, 2008b ; Garinis, 2008 ; Rieckher et al, 2021 ).…”

Section: Mouse Models For Dna Damage-driven Inflammationmentioning

confidence: 99%

DNA damage, inflammation and aging: Insights from mice

2022

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Persistent DNA lesions build up with aging triggering inflammation, the body’s first line of immune defense strategy against foreign pathogens and irritants. Once established, DNA damage-driven inflammation takes on a momentum of its own, due to the amplification and feedback loops of the immune system leading to cellular malfunction, tissue degenerative changes and metabolic complications. Here, we discuss the use of murine models with inborn defects in genome maintenance and the DNA damage response for understanding how irreparable DNA lesions are functionally linked to innate immune signaling highlighting their relevance for developing novel therapeutic strategies against the premature onset of aging-associated diseases.

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“…In line, trimethylation of H3K4 whose levels change with advancing age is not only associated with the promoters of highly transcribed genes but also with sites of newly generated DSBs (Faucher and Wellinger, 2010). Interestingly, in mouse adipocytes, the accumulation of irreparable DNA interstrand crosslinks triggers the substantial loss of repressive histones H3K9 and H3K27 trimethylation PTMs along with the concomitant increase of activating H3K9ac and H3K4m3 histone marks, facilitating the transcriptional derepression of senescence-associated proinflammatory signals (Karakasilioti and Garinis, 2014;Karakasilioti et al, 2013).…”

Section: Introductionmentioning

confidence: 99%