Molecular pathology of rare progeroid diseases

Rieckher, Matthias; Garinis, George A.; Schumacher, Björn

doi:10.1016/j.molmed.2021.06.011

Cited by 33 publications

(23 citation statements)

References 116 publications

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“…Overall, micronuclei and nuclear buds are major indexes for genome instability [2]. Nuclear envelope alterations induce genome instability and a constitutive DDR activation [63,64]. Chronic genomic instability causes cellular effects, including chromatin structural problems and changes in cell fate.…”

Section: Discussionmentioning

confidence: 99%

“…This situation induced cellular senescence, reduced regenerative capacity, altered metabolism, modified mitochondrial homeostasis, and the activation of systemic stress and proinflammatory responses. In fact, cellular senescence is a mechanism of response to chronic DNA damage described in a variety of Progeroid Syndromes, as well as natural aging [63].…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Murdocca

Spitalieri

Cappello

et al. 2022

Aging

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Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy is a rare, genetic, premature aging disease named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. In previous in vitro studies, we have already described several hallmarks of aging, including genetic damage, telomere shortening, cell senescence and proliferation defects. Since a clear connection has been reported between telomere shortening and mitochondria malfunction to initiate the aging process, we explored the role that mitochondrial metabolism and activity play in pathogenesis of MDPL Syndrome, an aspect that has not been addressed yet. We thus evaluated mtDNA copy number, assessing a significant decrease in mutated cells. The expression level of genes related to mitochondrial biogenesis and activity also revealed a significant reduction, highlighting a mitochondrial dysfunction in MDPL cells. Even the expression levels of mitochondrial marker SOD2, as assessed by immunofluorescence, were reduced. The decrease in this antioxidant enzyme correlated with increased production of mitochondrial ROS in MDPL cells, compared to WT. Consistent with these data, Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) analysis revealed in MDPL cells fewer mitochondria, which also displayed morphological abnormalities. Accordingly, we detected autophagic vacuoles containing partially digested mitochondria. Overall, our results demonstrate a dramatic impairment of mitochondrial biogenesis and activity in MDPL Syndrome. Administration of Metformin, though unable to restore mitochondrial impairment, proved efficient in rescuing nuclear abnormalities, suggesting its use to specifically ameliorate the premature aging phenotype.www.aging-us.com AGINGG0/G1 phase. Furthermore, telomere shortening was faster in MDPL cells, proposing their malfunction as a relevant trait in MDPL syndrome.Current papers have reported that telomere shortening may also influence mitochondria activity through many pathways to begin the aging process, among which the nuclear-mitochondrial signalling [3]. Adaptive response to such damage involves peroxisome proliferatoractivated receptor gamma co-activator 1a (PGC-1a), a master regulator of mitochondrial biogenesis and activity, which is activated by SIRT1. In turn, PGC-1a induces the expression of mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Murdocca

Spitalieri

Cappello

et al. 2022

Aging

View full text Add to dashboard Cite

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“…DNA damage includes oxidative modifications, single-and double-strand breaks (DSBs), and mutations, both in vitro and in vivo [12,13]. Many studies have indicated that DNA damage accumulation is associated with aging [14,15]. A complete DNA repair system is also established to repair DNA damage in cells.…”

Section: Dna Damage and Repairmentioning

confidence: 99%

Flavonoids—Natural Gifts to Promote Health and Longevity

Fan

Yang

et al. 2022

IJMS

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The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.

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“…Already in the 50s, it was proposed that aging could be initiated by a somatic mutation mechanism and that the spontaneous accumulation of somatic mutations in the genome was causative to aging (Failla, 1958 ; Szilard, 1959 ). In support of this theory, the so‐called segmental progeroid or accelerated aging syndromes, characterized by occurrence of age‐related phenotypes in kids or young adults, are prevalently caused by inherited mutations in genes involved in DNA repair and genome maintenance (Rieckher et al, 2021 ). More recently, the dramatic cellular response to DNA damage has been characterized and shown to induce other cellular defects contributing to aging, including senescence, epigenetic alterations, proteostatic stress, and mitochondrial dysfunction (Schumacher et al, 2021 ).…”

Section: The Somatic Mutation Theory Of Agingmentioning

confidence: 99%

Challenges of proving a causal role of somatic mutations in the aging process

2022

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We know the consequences of aging at the organismal level (defects of the cardiovascular system, reduction of cognitive function, osteoporosis, deregulation of immune system, graying/loss of hair, loss of skin tone, and subcutaneous fat) and at the cell and tissue level (senescence, inability to perform cell/tissue-specific function, reduced ability to repair damage, altered proteome, and capacity of energy production). However, we have not been able to convincingly establish whether aging is the product of multiple causes that necessarily co-occur or a cascade initiated by a primary event.The loss of genome integrity accompanies aging. As the DNA contains the instructions for all other processes in the cell, the idea that genomic changes could initiate other molecular modifications that participate in the aging phenotypes has fascinated generations of researchers. Already in the 50s, it was proposed that aging could be initiated by a somatic mutation mechanism and that the spontaneous accumulation of somatic mutations in the genome was causative to aging (Failla, 1958;Szilard, 1959). In support of this theory, the so-called segmental progeroid or accelerated aging syndromes, characterized by occurrence of age-related phenotypes in kids or young adults, are prevalently caused by inherited mutations in genes involved in DNA repair and genome maintenance (Rieckher et al., 2021). More recently, the dramatic cellular response to DNA damage

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Molecular pathology of rare progeroid diseases

Cited by 33 publications

References 116 publications

Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Flavonoids—Natural Gifts to Promote Health and Longevity

Challenges of proving a causal role of somatic mutations in the aging process

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