Progeria

Publication Title: 
Nature

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome.

Author(s): 
Niedernhofer, Laura J.
Garinis, George A.
Raams, Anja
Lalai, Astrid S.
Robinson, Andria Rasile
Appeldoorn, Esther
Odijk, Hanny
Oostendorp, Roos
Ahmad, Anwaar
van Leeuwen, Wibeke
Theil, Arjan F.
Vermeulen, Wim
van der Horst, Gijsbertus T. J.
Meinecke, Peter
Kleijer, Wim J.
Vijg, Jan
Jaspers, Nicolaas G. J.
Hoeijmakers, Jan H. J.
Publication Title: 
Human Molecular Genetics

Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster.

Author(s): 
MariÒo, Guillermo
Ugalde, Alejandro P.
Salvador-Montoliu, Natalia
Varela, Ignacio
QuirÛs, Pedro M.
CadiÒanos, Juan
van der Pluijm, Ingrid
Freije, JosÈ M. P.
LÛpez-OtÌn, Carlos
Publication Title: 
PLoS genetics

Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice.

Author(s): 
Schumacher, Bjˆrn
van der Pluijm, Ingrid
Moorhouse, Michael J.
Kosteas, Theodore
Robinson, Andria Rasile
Suh, Yousin
Breit, Timo M.
van Steeg, Harry
Niedernhofer, Laura J.
van Ijcken, Wilfred
Bartke, Andrzej
Spindler, Stephen R.
Hoeijmakers, Jan H. J.
van der Horst, Gijsbertus T. J.
Garinis, George A.
Publication Title: 
Nature Communications

With ageing, there is a loss of adult stem cell function. However, there is no direct evidence that this has a causal role in ageing-related decline. We tested this using muscle-derived stem/progenitor cells (MDSPCs) in a murine progeria model. Here we show that MDSPCs from old and progeroid mice are defective in proliferation and multilineage differentiation. Intraperitoneal administration of MDSPCs, isolated from young wild-type mice, to progeroid mice confer significant lifespan and healthspan extension.

Author(s): 
Lavasani, Mitra
Robinson, Andria R.
Lu, Aiping
Song, Minjung
Feduska, Joseph M.
Ahani, Bahar
Tilstra, Jeremy S.
Feldman, Chelsea H.
Robbins, Paul D.
Niedernhofer, Laura J.
Huard, Johnny
Publication Title: 
Cell

Human LMNA gene mutations result in laminopathies that include Emery-Dreifuss muscular dystrophy (AD-EDMD) and Hutchinson-Gilford progeria, the premature aging syndrome (HGPS). The Lmna null (Lmna(-/-)) and progeroid Lmna?9 mutant mice are models for AD-EDMD and HGPS, respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna(-/-) and Lmna?9 fibroblasts have typically misshapen nuclei.

Author(s): 
Chen, Chia-Yen
Chi, Ya-Hui
Mutalif, Rafidah Abdul
Starost, Matthew F.
Myers, Timothy G.
Anderson, Stasia A.
Stewart, Colin L.
Jeang, Kuan-Teh
Publication Title: 
Stem Cell Research & Therapy

Ageing is a biological certainty for all living organisms, and is due to the loss of tissue homeostasis and regenerative capacity (except for newts) in which somatic stem cells are thought to play an important role. Many ageing-associated dysfunctions in stem cells have been described, but it remains ambiguous whether these are merely an outcome of ageing or are causal. Parabiotic animal studies suggest there are factors in the systemic environment that can influence the regenerative capacity of tissues.

Author(s): 
McCullagh, Karl J. A.
Publication Title: 
Current Opinion in Cell Biology

The aging rate of an organism depends on the ratio of tissue degeneration to tissue repair. As a consequence, molecular alterations that tip this balance toward degeneration cause accelerated aging. Conversely, interventions can be pursued to reduce tissue degeneration or to increase tissue repair with the aim of delaying the onset of age-associated manifestations. Recent studies on the biology of stem cells in aging have revealed the influence of systemic factors on their functionality and demonstrated the feasibility of reprogramming aged and progeroid cells.

Author(s): 
Freije, JosÈ M. P.
LÛpez-OtÌn, Carlos
Publication Title: 
Cell Metabolism

Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A,†leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity.

Author(s): 
Liu, Baohua
Ghosh, Shrestha
Yang, Xi
Zheng, Huiling
Liu, Xinguang
Wang, Zimei
Jin, Guoxiang
Zheng, Bojian
Kennedy, Brian K.
Suh, Yousin
Kaeberlein, Matt
Tryggvason, Karl
Zhou, Zhongjun
Publication Title: 
Nature Communications

A de novo G608G mutation in LMNA gene leads to Hutchinson-Gilford progeria syndrome. Mice lacking the prelamin A-processing metalloprotease, Zmpste24, recapitulate many of the progeroid features of Hutchinson-Gilford progeria syndrome. Here we show that A-type lamins interact with SUV39H1, and prelamin A/progerin exhibits enhanced binding capacity to SUV39H1, protecting it from proteasomal degradation and, consequently, increasing H3K9me3 levels. Depletion of Suv39h1 reduces H3K9me3 levels, restores DNA repair capacity and delays senescence in progeroid cells.

Author(s): 
Liu, Baohua
Wang, Zimei
Zhang, Le
Ghosh, Shrestha
Zheng, Huiling
Zhou, Zhongjun
Publication Title: 
Scientific American
Author(s): 
Rose, M. R.

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