Volume 6, Issue 11

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Buffenstein R, Nelson OL, Corbit KC, . Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform. Aging (Albany NY). 6:913-920. https://doi.org/10.18632/aging.100704

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Provider: TY - JOUR AU - Buffenstein, Rochelle AU - Nelson, O. Lynne AU - Corbit, Kevin C. TI - Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100704 DO - 10.18632/aging.100704 SP - 913 EP - 920 PY - ER -

Provider: TY - JOUR AU - Buffenstein, Rochelle AU - Nelson, O. Lynne AU - Corbit, Kevin C. TI - Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100704 DO - 10.18632/aging.100704 SP - 913 EP - 920 PY - AB - The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development –rodent models – and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work. ER -

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Agostini M, Niklison-Chirou MV, Catani MV, Knight RA, Melino G, Rufini A, . TAp73 promotes anti-senescence-anabolism not proliferation. Aging (Albany NY). 6:921-930. https://doi.org/10.18632/aging.100701

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Provider: TY - JOUR AU - Agostini, Massimiliano AU - Niklison-Chirou, Maria Victoria AU - Catani, Maria Valeria AU - Knight, Richard A. AU - Melino, Gerry AU - Rufini, Alessandro TI - TAp73 promotes anti-senescence-anabolism not proliferation JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100701 DO - 10.18632/aging.100701 SP - 921 EP - 930 PY - ER -

Provider: TY - JOUR AU - Agostini, Massimiliano AU - Niklison-Chirou, Maria Victoria AU - Catani, Maria Valeria AU - Knight, Richard A. AU - Melino, Gerry AU - Rufini, Alessandro TI - TAp73 promotes anti-senescence-anabolism not proliferation JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100701 DO - 10.18632/aging.100701 SP - 921 EP - 930 PY - AB - TAp73, a member of the p53 family, has been traditionally considered a tumor suppressor gene, but a recent report has claimed that it can promote cellular proliferation. This assumption is based on biochemical evidence of activation of anabolic metabolism, with enhanced pentose phosphate shunt (PPP) and nucleotide biosynthesis. Here, while we confirm that TAp73 expression enhances anabolism, we also substantiate its role in inhibiting proliferation and promoting cell death. Hence, we would like to propose an alternative interpretation of the accumulating data linking p73 to cellular metabolism: we suggest that TAp73 promotes anabolism to counteract cellular senescence rather than to support proliferation. ER -

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Bernal GM, Wahlstrom JS, Crawley CD, Cahill KE, Pytel P, Liang H, Kang S, Weichselbaum RR, Yamini B, . Loss of Nfkb1 leads to early onset aging. Aging (Albany NY). 6:931-942. https://doi.org/10.18632/aging.100702

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Provider: TY - JOUR AU - Bernal, Giovanna M. AU - Wahlstrom, Joshua S. AU - Crawley, Clayton D. AU - Cahill, Kirk E. AU - Pytel, Peter AU - Liang, Hua AU - Kang, Shijun AU - Weichselbaum, Ralph R. AU - Yamini, Bakhtiar TI - Loss of <i>Nfkb1</i> leads to early onset aging JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100702 DO - 10.18632/aging.100702 SP - 931 EP - 942 PY - ER -

Provider: TY - JOUR AU - Bernal, Giovanna M. AU - Wahlstrom, Joshua S. AU - Crawley, Clayton D. AU - Cahill, Kirk E. AU - Pytel, Peter AU - Liang, Hua AU - Kang, Shijun AU - Weichselbaum, Ralph R. AU - Yamini, Bakhtiar TI - Loss of <i>Nfkb1</i> leads to early onset aging JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100702 DO - 10.18632/aging.100702 SP - 931 EP - 942 PY - AB - NF-(B is a major regulator of age-dependent gene expression and the p50/NF-(B1 subunit is an integral modulator of NF-(B signaling. Here, we examined Nfkb1−/− mice to investigate the relationship between this subunit and aging. Although Nfkb1−/− mice appear similar to littermates at six months of age, by 12 months they have a higher incidence of several observable age-related phenotypes. In addition, aged Nfkb1−/− animals have increased kyphosis, decreased cortical bone, increased brain GFAP staining and a decrease in overall lifespan compared to Nfkb1+/+. In vitro, serially passaged primary Nfkb1−/− MEFs have more senescent cells than comparable Nfkb1+/+ MEFs. Also, Nfkb1−/− MEFs have greater amounts of phospho-H2AX foci and lower levels of spontaneous apoptosis than Nfkb1+/+, findings that are mirrored in the brains of Nfkb1−/− animals compared to Nfkb1+/+. Finally, in wildtype animals a substantial decrease in p50 DNA binding is seen in aged tissue compared to young. Together, these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-(B pathway and mammalian aging. ER -

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He Y, Lu X, Yang L, Xu L, Kong Q, . Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians. Aging (Albany NY). 6:944-951. https://doi.org/10.18632/aging.100703

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Provider: TY - JOUR AU - He, Yong-Han AU - Lu, Xiang AU - Yang, Li-Qin AU - Xu, Liang-You AU - Kong, Qing-Peng TI - Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100703 DO - 10.18632/aging.100703 SP - 944 EP - 951 PY - ER -

Provider: TY - JOUR AU - He, Yong-Han AU - Lu, Xiang AU - Yang, Li-Qin AU - Xu, Liang-You AU - Kong, Qing-Peng TI - Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100703 DO - 10.18632/aging.100703 SP - 944 EP - 951 PY - AB - Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population. ER -

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Bektas A, Zhang Y, Lehmann E, Wood WH, Becker KG, Madara K, Ferrucci L, Sen R, . Age-associated changes in basal NF-κB function in human CD4⁺ T lymphocytes via dysregulation of PI3 kinase. Aging (Albany NY). 6:957-969. https://doi.org/10.18632/aging.100705

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Provider: TY - JOUR AU - Bektas, Arsun AU - Zhang, Yongqing AU - Lehmann, Elin AU - Wood, William H. AU - Becker, Kevin G. AU - Madara, Karen AU - Ferrucci, Luigi AU - Sen, Ranjan TI - Age-associated changes in basal NF-κB function in human CD4⁺ T lymphocytes via dysregulation of PI3 kinase JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100705 DO - 10.18632/aging.100705 SP - 957 EP - 969 PY - ER -

Provider: TY - JOUR AU - Bektas, Arsun AU - Zhang, Yongqing AU - Lehmann, Elin AU - Wood, William H. AU - Becker, Kevin G. AU - Madara, Karen AU - Ferrucci, Luigi AU - Sen, Ranjan TI - Age-associated changes in basal NF-κB function in human CD4⁺ T lymphocytes via dysregulation of PI3 kinase JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100705 DO - 10.18632/aging.100705 SP - 957 EP - 969 PY - AB - Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-κB is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-κB-associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-κB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-κB activity may contribute to the mild pro-inflammatory state of aging. ER -

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Klang IM, Schilling B, Sorensen DJ, Sahu AK, Kapahi P, Andersen JK, Swoboda P, Killilea DW, Gibson BW, Lithgow GJ, . Iron promotes protein insolubility and aging in C. elegans. Aging (Albany NY). 6:975-988. https://doi.org/10.18632/aging.100689

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Provider: TY - JOUR AU - Klang, Ida M. AU - Schilling, Birgit AU - Sorensen, Dylan J. AU - Sahu, Alexandria K. AU - Kapahi, Pankaj AU - Andersen, Julie K. AU - Swoboda, Peter AU - Killilea, David W. AU - Gibson, Bradford W. AU - Lithgow, Gordon J. TI - Iron promotes protein insolubility and aging in <i>C. elegans</i> JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100689 DO - 10.18632/aging.100689 SP - 975 EP - 988 PY - ER -

Provider: TY - JOUR AU - Klang, Ida M. AU - Schilling, Birgit AU - Sorensen, Dylan J. AU - Sahu, Alexandria K. AU - Kapahi, Pankaj AU - Andersen, Julie K. AU - Swoboda, Peter AU - Killilea, David W. AU - Gibson, Bradford W. AU - Lithgow, Gordon J. TI - Iron promotes protein insolubility and aging in <i>C. elegans</i> JO - JA - Aging (Albany NY) VL - 6 IS - 11 PB - SN - UR - https://doi.org/10.18632/aging.100689 DO - 10.18632/aging.100689 SP - 975 EP - 988 PY - AB - Many late-onset proteotoxic diseases are accompanied by a disruption in homeostasis of metals (metallostasis) including iron, copper and zinc. Although aging is the most prominent risk factor for these disorders, the impact of aging on metallostasis and its role in proteotoxic disease remain poorly understood. Moreover, it is not clear whether a loss of metallostasis influences normal aging. We have investigated the role of metallostasis in longevity of Caenorhabditis elegans. We found that calcium, copper, iron, and manganese levels increase as a function of age, while potassium and phosphorus levels tend to decrease. Increased dietary iron significantly accelerated the age-related accumulation of insoluble protein, a molecular pathology of aging. Proteomic analysis revealed widespread effects of dietary iron in multiple organelles and tissues. Pharmacological interventions to block accumulation of specific metals attenuated many models of proteotoxicity and extended normal lifespan. Collectively, these results suggest that a loss of metallostasis with aging contributes to age-related protein aggregation. ER -

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