Sociality, Hierarchy, Health Comparative Biodemography: A Collection of Papers (2014) / Chapter Skim
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3 Genes Revisited: The Biodemography of Social Environmental Variation Through a Functional Genomics Lens--Jenny Tung
3 Genes Revisited: The Biodemography of Social Environmental Variation Through a Functional Genomics Lens--Jenny Tung
Pages 39-64
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From page 39... ...
Finally, targeted manipulations of individual genes in laboratory model organisms have pinpointed specific mutations that have strong effects on longevity. Mutations in the insulin-like growth factor receptor gene daf-2 in the worm Caenorhabditis elegans, for example, result in a more than 2-fold increase in lifespan (Kenyon et al., 1993)
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From page 40... ...
. For example, such approaches can be used to investigate which genes are mutually affected by social adversity and age, how gene regulation contributes to social environmental effects on health, and whether gene regulatory responses to social stressors vary across species in a predictable manner.
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From page 41... ...
Hence, functional genomics is closely tied to the study of gene regulation, and adopting a functional genomic strategy to study aging relies on the assumption that changes in gene regulation are an important component of the aging process. Support for this assumption comes from several independent sources.
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From page 42... ...
. While other gene regulatory phenotypes have been less well studied in relation to age, where data are available, they show similar patterns (Christensen et al., 2009; Fraga, 2009; Han et al., 2012)
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From page 43... ...
Gene regulatory phenotypes -- measurements that capture variation in gene regulation, including gene expression levels and epigenetic marks -- can thus provide a useful common currency for studying how social experiences influence aging-related genes. While studies of single genes or small sets of genes can take advantage of this approach as well, it can be particularly valuable when applied to genome-scale datasets (see Box 3-1)
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From page 44... ...
Sample quantity. Many approaches for measuring genome-wide gene regulatory phenotypes are able to utilize very small amounts of sample (e.g., < 50 uL of blood)
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From page 45... ...
. Instead, similarities are primarily observable at the level of functionally related gene sets: advanced age is consistently assoiated with downregulation of genes involved in energy metabolism c and upregulation of genes involved in the immune response, apoptosis, and insulin-like growth factor binding (de Magalhães et al., 2009)
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From page 46... ...
The first involves using biodemographic observations as a motivation for functional genomic studies, with the aim of understanding how, and in what contexts, gene regulatory changes with age intersect with gene regulatory effects of the social environment. The second involves development of a tighter integration between functional genomics and biodemography, in which demographic concepts of mortality rates and senescence can be leveraged to investigate the role of gene regulation in aging.
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From page 47... ...
Circumstantially, it makes sense that gene regulatory changes in response to social adversity are related to aging. Aging-related genes and pathways are often involved in the response to environmental stressors.
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From page 48... ...
Consistent with comparisons between disparate aging datasets, similarities between gene expression changes with age and the gene expression effects of social status were stronger for functionally coherent gene sets than for single loci. For example, genes involved in insulin growth factor I signaling and genes involved in inflammation -- two processes tightly associated with aging -- were identified in both the human age-associated (Göring et al., 2007)
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From page 49... ...
Similarly, studies of the gene regulatory response to social adversity frequently identify genes involved in intercellular communication, a second major hallmark of aging. These genes include the cellular targets of steroid hormone and sympathetic nervous system signaling and, most consistently, genes involved in the inflammatory response.
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From page 50... ...
. A focus on the regulation of specific aging-related pathways therefore promises to improve the understanding of how social environmental effects influence the aging process.
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From page 51... ...
In addition to investigating conserved social environmental signatures (either between studies or with signatures of age) , functional genomic studies can also be used to dissect context-specific effects.
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From page 52... ...
A good place to start would be in discriminating the gene regulatory consequences of social status versus social isolation -- two distinct sources of social adversity that are often discussed together, but that need not be correlated. Functional genomic data would help resolve whether, and to what degree, social status and social integration act additively or nonadditively, as well as whether additive effects arise because they affect different molecular mechanisms.
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From page 53... ...
. Defining whether a given social environmental variable influences the Gompertz intercept or the Gompertz slope can therefore provide a useful framework for testing the relationship between social adversity, aging, and putative functional genomic biomarkers of both processes.
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From page 54... ...
However, AGE accumulation did not change in association with the imposition of dietary restriction, which only influenced initial mortality rate. As the number of putative gene regulatory biomarkers of both the social environment and aging accumulates, it should be possible to perform similar kinds of analyses to support or refute the likelihood that individual markers of social adversity are mechanistically connected to aging.
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From page 55... ...
suggested that mechanistic links between a given trait and the aging process could be indicated when the shape of the relationship between age and that trait mirrored the shape of the relationship between age and mortality rate. To investigate this possibility will require moving away from testing simple linear relationships between age and gene regulatory traits towards investigating whether they, too, can be modeled using non-linear functions like the Gompertz.
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From page 56... ...
both chronological age and demographically defined senescence are associated with variation in genome-wide gene regulatory phenotypes; (2) key aspects of the social environment associated with health and longevity also impact gene regulation, particularly gene expression and DNA methylation levels; and (3)
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From page 57... ...
While captive populations and lab models have thus provided important proof of principle that social environmental variation can impact gene regulation, they explain little about its effects in naturally aging populations. What social status and social integration mean to wild animals may differ from their meaning to captive animals; indeed, some types of social adversity tested in captivity, such as extended maternal separation or peer-rearing conditions, have no analogue in natural populations.
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From page 58... ...
Variation in the social environment clearly accounts for some of these effects, and probably exerts its influence in part through altering the regulation of genes. Functional genomic approaches suggest strategies for investigating this relationship through either biodemographically motivated or biodemographically integrated approaches.
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From page 59... ...
. Transcriptional modulation of the developing immune system by early life social adversity.
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From page 60... ...
. DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera.
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From page 61... ...
. Factors underlying variable DNA methylation in a human community cohort.
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From page 62... ...
. Beyond the evolutionary theory of ageing, from functional genomics to evo-gero.
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From page 63... ...
. Social environmental effects on gene regulation.
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