Shared Phenotypes Among Segmental Progeroid Syndromes Suggest Underlying Pathways of Aging

University of Rome Tor Vergata, Roma, Latium, Italy
The Journals of Gerontology Series A Biological Sciences and Medical Sciences (Impact Factor: 5.42). 02/2005; 60(1):10-20. DOI: 10.1093/gerona/60.1.10
Source: PubMed


Segmental progeroid syndromes are those whose phenotypes resemble accelerated aging. Here we analyze those phenotypes and hypothesize that short telomeres produce the same group of symptoms in a variety of otherwise unrelated progeroid syndromes. Specific findings are the following: (a) short telomeres in some progeroid syndromes cause an alopecia/osteoporosis/fingernail-atrophy group of symptoms; (b) fingernail atrophy in progeroid syndromes resembles the natural slowing of nail growth that occurs in normal aging and nail growth velocity, and may be a marker of replicative aging in keratinocyte stem cells; (c) alopecia and reduced hair diameter parallel the nail results; (d) osteoporosis in Dyskeratosis Congenita resembles age-related osteoporosis, but the same is not true of other progerias; and (e) gray hair is associated with short telomeres, but may also involve reactive oxygen species. On the basis of these results, we make several predictions and discuss how the segmental quality of progeroid syndromes may provide insight into normative aging.

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Available from: Jerry W Shay, Feb 07, 2016
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    • "The differential activation of p38 in fibroblasts from the different PSs may correlate with, or indeed influence, the in vivo progeroid phenotypes seen, as the progeroid features are less pronounced in NBS compared to either WS or ATR-SS. In addition, a feature of both WS and ATR-SS is the presence of inflammatory conditions such as type II diabetes (Rauch 2011; Martin et al. 1999), which is in contrast to NBS where inflammatory conditions are not found (Hofer et al. 2005); activated p38 is strongly associated with inflammatory conditions (Kumar et al. 2003). It is also possible, if activation of p38/MK2 and premature cellular senescence do play a role in the aged features of these syndromes, that p38 and/or MK2 inhibitors may be a therapeutic possibility (Davis and Kipling 2006). "
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    ABSTRACT: Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBNp70) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal fibroblasts. A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2. These data suggest that NBNp70 expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome. Electronic supplementary material The online version of this article (doi:10.1007/s10522-014-9530-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jan 2015 · Biogerontology
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    • "In addition to a strong genetic basis (Broer et al. 2013), this variation has been linked to differences in lifestyle (Monaghan & Haussmann 2006; Bakaysa et al. 2007). Short telomeres have been associated with premature ageing syndromes (Chang et al. 2004; Hofer et al. 2005) and reduced survival in humans (Boonekamp et al. 2013), nematodes (Joeng et al. 2004) and birds (Haussmann et al. 2005; Bize et al. 2009; Salomons et al. 2009; Angelier et al. 2013; Barrett et al. 2013). Thus, evidence is accumulating that telomere length is a biomarker of health and remaining lifespan. "
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    ABSTRACT: Telomeres, DNA-protein structures at chromosome ends, shorten with age and telomere length has been linked to age-related diseases and survival. In-vitro studies revealed that the shortest telomeres trigger cell senescence, but whether the shortest telomeres are also the best biomarker of ageing is not known. We measured telomeres in erythrocytes of wild common terns Sterna hirundo using terminal restriction fragment analysis. This yields a distribution of telomere lengths for each sample, and we investigated how different telomere subpopulations (percentiles) varied in their relation to age and fitness proxies. Longer telomeres within a genome lost more base pairs with age, and were better predictors of survival than shorter telomeres. Likewise, fitness proxies such as arrival date at the breeding grounds and reproductive success were best predicted by telomere length at the higher percentiles. Our finding that longer telomeres within a genome predict fitness components better than the shorter telomeres indicates that they are a more informative ageing biomarker. This finding contrasts with the fact that cell senescence is triggered by the shortest telomeres. We suggest that this paradox arises, because longer telomeres lose more base pairs per unit time and thus better reflect the various forms of stress that accelerate telomere shortening, and that telomeres primarily function as biomarker because their shortening reflects cumulative effects of various stressors rather than reflecting telomere induced cell senescence. This article is protected by copyright. All rights reserved.
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    • "That the low level of SIPS in RTS cells does not lead to major proliferative defects in fibroblasts does not preclude a role of SIPS in RTS. Indeed, the progeroid features seen in RTS are mild compared to WS (Hofer et al. 2005) and parallel the lower level of SIPS seen in RTS cells in culture. In contrast, the much reduced lifespan and high levels of SIPS seen in WS fibroblasts parallel the more severe progeroid features for WS that include the inflammatory conditions of atherosclerosis and type II diabetes (Davis and Kipling 2006). "
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    ABSTRACT: Rothmund–Thomson fibroblasts had replicative lifespans and growth rates within the range for normal fibroblasts; however, they show elevated levels of the stress-associated p38 MAP kinase, suggestive of stress during growth. Treatment with the p38 MAP kinase inhibitor SB203580 increased both lifespan and growth rate, as did reduction of oxidative stress using low oxygen in some strains. At replicative senescence p53, p21WAF1 and p16INK4A levels were elevated, and abrogation of p53 using shRNA knockdown allowed the cells to bypass senescence. Ectopic expression of human telomerase allowed Rothmund–Thomson fibroblasts to bypass senescence. However, activated p38 was still present, and continuous growth for some telomerised clones required either a reduction in oxidative stress or SB203580 treatment. Overall, the evidence suggests that replicative senescence in Rothmund–Thomson cells resembles normal senescence in that it is telomere driven and p53 dependent. However, the lack of RECQL4 leads to enhanced levels of stress during cell growth that may lead to moderate levels of stress-induced premature senescence. As replicative senescence is believed to underlie human ageing, a moderate level of stress-induced premature senescence and p38 activity may play a role in the relatively mild ageing phenotype seen in Rothmund–Thomson. Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9476-9) contains supplementary material, which is available to authorized users.
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