Summary
The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of ...aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF‐I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro‐longevity effects and ability of these interventions to prevent or delay multiple age‐related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.
Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome ...instability (W-CIN) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features (SAFs). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion.
The genome of multicellular organisms carries the hereditary information necessary for the development of all organs and tissues and to maintain function in adulthood. To ensure the genetic stability ...of the species, genomes are protected against changes in sequence information. However, genomes are not static.
mutations in germline cells are passed on to offspring and generate the variation needed in evolution. Moreover, postzygotic mutations occur in all somatic cells during development and aging. These somatic mutations remain limited to the individual, generating tissues that are genome mosaics. Insight into such mutations and their consequences has been limited due to their extremely low abundance, with most mutations unique for each cell. Recent advances in sequencing, including whole genome sequencing at the single-cell level, have now led to the first insights into somatic mutation burdens in human tissues. Here, we will first briefly describe the latest methodology for somatic mutation analysis, then review our current knowledge of somatic mutation burden in human tissues and, finally, briefly discuss the possible functional impact of somatic mutations on the aging process and age-related diseases, including cancer and diseases other than cancer.
Signalling pathway activation analysis is a powerful approach for extracting biologically relevant features from large-scale transcriptomic and proteomic data. However, modern pathway-based methods ...often fail to provide stable pathway signatures of a specific phenotype or reliable disease biomarkers. In the present study, we introduce the in silico Pathway Activation Network Decomposition Analysis (iPANDA) as a scalable robust method for biomarker identification using gene expression data. The iPANDA method combines precalculated gene coexpression data with gene importance factors based on the degree of differential gene expression and pathway topology decomposition for obtaining pathway activation scores. Using Microarray Analysis Quality Control (MAQC) data sets and pretreatment data on Taxol-based neoadjuvant breast cancer therapy from multiple sources, we demonstrate that iPANDA provides significant noise reduction in transcriptomic data and identifies highly robust sets of biologically relevant pathway signatures. We successfully apply iPANDA for stratifying breast cancer patients according to their sensitivity to neoadjuvant therapy.
Chromosomal aneuploidy in the aging brain Faggioli, Francesca; Vijg, Jan; Montagna, Cristina
Mechanisms of ageing and development,
08/2011, Letnik:
132, Številka:
8
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
► Whole chromosome aneuploidy is a common feature observed in the development of the mammalian nervous system. ► Aneuploidy is a mechanism that could generate genetic diversity. ► Aneuploidy is ...observed in the adult brain but at lower frequency then during development. ► Aneuploidy has been shown to be associated to neurodegenerative disorders and age related syndromes.
Mechanisms that govern genome integrity and stability are major guarantors of viability and longevity. As people age, memory and the ability to carry out tasks often decline and their risk for neurodegenerative diseases increases. The biological mechanisms underlying this age-related neuronal decline are not well understood. Genome instability has been implicated in neurodegenerative processes in aging and disease. Aneuploidy, a chromosome content that deviates from a diploid genome, is a recognized form of genomic instability. Here, we will review chromosomal aneuploidy in the aging brain, its possible causes, its consequences for cellular homeostasis and its possible link to functional decline and neuropathies.
Significance The naked mole rat is a longest lived and cancer-resistant rodent. Tumor resistance in the naked mole rat is mediated by signals from the extracellular matrix component hyaluronan ...triggering the induction of INK4 (inhibitors of cyclin dependent kinase 4) locus expression. The human and mouse INK4 locus encodes three critical tumor-suppressor proteins, p15 ᴵᴺᴷ⁴ᵇ, ARF (alternate reading frame), and p16 ᴵᴺᴷ⁴ᵃ, which are among the most frequently mutated in cancer. Furthermore, p16 ᴵᴺᴷ⁴ᵃ is implicated in aging and senescence. Here, we show that the naked mole rat INK4 locus encodes an additional product, a hybrid between p15 ᴵᴺᴷ⁴ᵇ and p16 ᴵᴺᴷ⁴ᵃ. The novel product, named pALT ᴵᴺᴷ⁴ᵃ/ᵇ, may contribute to tumor resistance and longevity of the naked mole rat. Understanding the regulation of the INK4 locus is critical for cancer and aging research.
The naked mole rat ( Heterocephalus glaber ) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15 ᴵᴺᴷ⁴ᵇ, p16 ᴵᴺᴷ⁴ᵃ, and ARF (alternate reading frame). Although p15 ᴵᴺᴷ⁴ᵇ has its own ORF, p16 ᴵᴺᴷ⁴ᵃ and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15 ᴵᴺᴷ⁴ᵇ exon 1 joined to p16 ᴵᴺᴷ⁴ᵃ exons 2 and 3. We have named this isoform pALT ᴵᴺᴷ⁴ᵃ/ᵇ (for alternative splicing). We show that pALT ᴵᴺᴷ⁴ᵃ/ᵇ is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALT ᴵᴺᴷ⁴ᵃ/ᵇ expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substrate attachment, and expression of oncogenes. When overexpressed in naked mole rat or human cells, pALT ᴵᴺᴷ⁴ᵃ/ᵇ has stronger ability to induce cell-cycle arrest than either p15 ᴵᴺᴷ⁴ᵇ or p16 ᴵᴺᴷ⁴ᵃ. We hypothesize that the presence of the fourth product, pALT ᴵᴺᴷ⁴ᵃ/ᵇ of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.
Inherited germline mutations in the breast cancer gene 1 (BRCA1) or BRCA2 genes (herein BRCA1/2) greatly increase the risk of breast and ovarian cancer, presumably by elevating somatic mutational ...errors as a consequence of deficient DNA repair. However, this has never been directly demonstrated by a comprehensive analysis of the somatic mutational landscape of primary, noncancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1/2 germline mutations. Here, we used an accurate, single-cell whole-genome sequencing approach to first show that telomerized primary mammary epithelial cells heterozygous for a highly penetrant BRCA1 variant displayed a robustly elevated mutation frequency as compared with their isogenic control cells. We then demonstrated a small but statistically significant increase in mutation frequency in mammary epithelial cells isolated from the breast of BRCA1/2 mutation carriers as compared with those obtained from age-matched controls with no genetically increased risk for breast cancer.
Aging and Genome Maintenance: Lessons from the Mouse? Hasty, Paul; Campisi, Judith; Hoeijmakers, Jan ...
Science (American Association for the Advancement of Science),
02/2003, Letnik:
299, Številka:
5611
Journal Article
Recenzirano
Recent progress in the science of aging is driven largely by the use of model systems, ranging from yeast and nematodes to mice. These models have revealed conservation in genetic pathways that ...balance energy production and its damaging by-products with pathways that preserve somatic maintenance. Maintaining genome integrity has emerged as a major factor in longevity and cell viability. Here we discuss the use of mouse models with defects in genome maintenance for under-standing the molecular basis of aging in humans.
Driven by technological progress, human life expectancy has increased greatly since the nineteenth century. Demographic evidence has revealed an ongoing reduction in old-age mortality and a rise of ...the maximum age at death, which may gradually extend human longevity. Together with observations that lifespan in various animal species is flexible and can be increased by genetic or pharmaceutical intervention, these results have led to suggestions that longevity may not be subject to strict, species-specific genetic constraints. Here, by analysing global demographic data, we show that improvements in survival with age tend to decline after age 100, and that the age at death of the world's oldest person has not increased since the 1990s. Our results strongly suggest that the maximum lifespan of humans is fixed and subject to natural constraints.
Genetics of longevity and aging Vijg, Jan; Suh, Yousin
Annual review of medicine,
01/2005, Letnik:
56, Številka:
1
Journal Article
Recenzirano
Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of ...organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of genes, corresponding to entire gene functional modules, will be assessed for all possible sequence variation and associated with detailed phenotypic information on each individual over extended periods of time. This should eventually unravel the genetic factors that contribute to each particular aging phenotype.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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