Heightened Induction of Proapoptotic Signals in Response to Endoplasmic Reticulum Stress in Primary Fibroblasts from a Mouse Model of Longevity

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2011; 286(35):30344-51. DOI: 10.1074/jbc.M111.220541
Source: PubMed


Previous work from our laboratory has shown that primary fibroblasts from long-lived Snell dwarf mice display a higher sensitivity to the lethal effects of endoplasmic reticulum (ER) stressors, such as thapsigargin, than cells from normal mice. Here we show that thapsigargin induces higher expression of CHOP, enhanced cleavage of caspase-12, higher caspase-3 activity, and increased phosphorylation of c-JUN, all indicators of enhanced apoptosis, in dwarf fibroblasts. Dwarf and normal fibroblasts show no genotypic difference in up-regulating BiP, GRP94, and ERp72 proteins after exposure to thapsigargin. However, dwarf fibroblasts express lower basal levels of a number of putative XBP1 target genes including Armet, Edem1, Erdj3, p58(IPK) and Sec61a1, as well as Ire1α itself. Furthermore, when exposed to thapsigargin, dwarf fibroblasts display attenuated splicing of Xbp1, but similar phosphorylation of eIF2α, in comparison to normal fibroblasts. These data support the notion that IRE1/XBP1 signaling is set at a lower level in dwarf fibroblasts. Diminished Xbp1 splicing in dwarf-derived fibroblasts may tilt the balance between prosurvival and proapoptotic signals in favor of apoptosis, thereby leading to higher induction of proapoptotic signals in these cells and ultimately their increased sensitivity to ER stressors. These results, together with recent findings in Caenorhabditis elegans daf-2 mutants, point to a potential interplay between insulin/IGF-1 signals and unfolded protein response signaling.

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    • "The candidate SY genes in this study do not clearly overlap with known longevity genes in humans. However, EDEM1 levels appear to be lower in a dwarf mouse model for longevity that also possesses lower levels of IGF1, suggesting a possible connection between IGF1 and EDEM1 that merits further study (Akha et al., 2011). Interestingly, a recent GWAS on facial photoaging suggested an association with an SNP in linkage disequilibrium with FBXO40, which can modulate the IGF1 pathway (Le Clerc et al., 2013), a regulator of human longevity and lifespan in animal models (van Heemst et al., 2005). "
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    ABSTRACT: To identify genes that promote facial skin youthfulness (SY), a genome-wide association study on an Ashkenazi-Jewish discovery group (n=428) was performed using Affymetrix 6.0 Single Nucleotide Polyorphism (SNP) Array. After SNP quality controls, 901,470 SNPs remained for analysis. Eigenstrat method showed no stratification. Cases and controls were identified by global facial skin aging severity including intrinsic and extrinsic parameters. Linear regression adjusted for age and gender, with no significant differences in smoking history, body mass index, menopausal status or personal or family history of centenarians. Six SNPs met the Bonferroni threshold with pallele <10(-8); 2 of these 6 had pgenotype<10(-8). Quantitative trait loci mapping confirmed linkage disequilibrium. The 6 SNPs were interrogated by MassARRAY in a replication group (n=436) with confirmation of rs6975107, an intronic region of KCND2 (pgenotype=0.023). A second replication group (n=371) confirmed rs318125, downstream of DIAPH2 (pallele=0.010, pgenotype=0.002) and rs7616661, downstream of EDEM1 (pgenotype=0.042). DIAPH2 has been associated with premature ovarian insufficiency, an aging phenotype in humans. EDEM1 associates with lifespan in animal models, though not humans. KCND2 is expressed in human skin, but has not been associated with aging. These genes represent new candidate genes to study the molecular basis of healthy skin aging.Journal of Investigative Dermatology accepted article preview online, 13 September 2013. doi:10.1038/jid.2013.381.
    Journal of Investigative Dermatology 09/2013; 134(3). DOI:10.1038/jid.2013.381 · 7.22 Impact Factor
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    • "Misfolded proteins, whether a consequence of aging, toxins, hypoxic, oxidative, or ischemic stress, signal cell death damage, proapoptosis responses, that impact longevity, and disease states. HSP 70 heat shock protein is a major rescue response to damage that impacts longevity [20, 21], vulnerability, and progression of AD neuronal pathology. Hormetic agents are candidates to intervene in proteotoxic damage and associated clinical symptoms [22, 23] and are identified here. "
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    ABSTRACT: Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS), diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer's Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer's disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or engineered, can "trick" activation of expression patterns of repair and rejuvenation. Examples of known candidate triggers of heat response, endogenous antioxidants, DNA repair, exercise, hibernation, and telomeres are available for AD intervention trials. Telomeres and telomerase emerge as major regulators in crossroads of senescence, cancer, and rejuvenation responsive to mimetics of telomeres. Lessons emerge from transgenic rodent models, the long-lived mole rat, clinical studies, and conserved innate pathways of stress resistance. Cross-reaction of benefits of different triggers promises intervention into seemingly otherwise unrelated diseases.
    International Journal of Alzheimer's Disease 05/2012; 2012:684283. DOI:10.1155/2012/684283
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    ABSTRACT: The mouse has become the favorite mammalian model. Among the many reasons for this privileged position of mice is their genetic proximity to humans, the possibilities of genetically manipulating their genomes and the availability of many tools, mutants and inbred strains. Also in the field of aging, mice have become very robust and reliable research tools. Since laboratory mice have a life expectancy of only a few years, genetic approaches and other strategies for intervening in aging can be tested by examining their effects on life span and aging parameters during the relatively short period of, for example, a PhD project. Moreover, experiments on mice with an extended life span as well as on mice demonstrating signs of (segmental) premature aging, together with genetic mapping strategies, have provided novel insights into the fundamental processes that drive aging. Finally, the results of studies on caloric restriction and pharmacological anti-aging treatments in mice have a high degree of relevance to humans. In this paper, we review a number of recent genetic mapping studies that have yielded novel insights into the aging process. We discuss the value of the mouse as a model for testing interventions in aging, such as caloric restriction, and we critically discuss mouse strains with an extended or a shortened life span as models of aging.
    Ageing research reviews 04/2012; 12(1):8-21. DOI:10.1016/j.arr.2012.03.010 · 4.94 Impact Factor
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