It is well known that gene expression becomes disarrayed in cells in old tissues. Mechanisms controlling the structure of nuclear DNA become dysfunctional, and that can unleash all sorts of errant protein production by allowing the machinery of gene expression to reach sections of the genome that are normally folded away and inaccessible. Recent work suggests that cycles of DNA double strand break repair may be close to the root of the cause of this, but it is undoubtedly far from simple as a process. Impaired gene expression control likely results in a feedback loop causing further impairment in gene expression control. Increased activity of transposons is one consequence of a failure to repress expression across the genome. There will be countless others.
The interesting question is the degree to which this matters in comparison to other mechanisms of aging. That is a hard question to answer. It is easier to identify and explore a specific mechanisms than it is to correct it in isolation of all other aspects of cellular biochemistry, and thus gain some insight into how much damage it causes. Very few mechanisms of aging can be corrected in that way, and specific portions of the age-related disarray of gene expression are not yet in that list. Still, researchers here make a good effort to connect disarray in gene expression with the mechanisms of cellular senescence and inflammatory signaling in aging, where the research community does have a better grasp on the likely relative importance to aging.
Cellular aging is characterized by disruption of the nuclear lamina and its associated heterochromatin. How these structural changes within the nucleus contribute to age-related degeneration of the organism is unclear. Genes lacking CpG islands (CGI- genes) generally associate with heterochromatin when they are inactive. Here, we show that the expression of these genes is globally activated in aged cells and tissues.
We show that in humans and mouse models, global up-regulation of CGI- gene expression is a hallmark of normal and pathological aging. CGI- gene misexpression plays a central role in age-associated degenerative changes by penetrating and interconnecting previously established hallmarks of aging: disruption of nuclear architecture and epigenetic alterations in aged or senescent cells are tightly associated with CGI- gene up-regulation, which, in turn, disturbs intercellular communication. Moreover, CGI- gene misexpression provides insights into the underlying molecular mechanisms of various phenomena observed in aged cells, including global loss of functional identity and increased transcriptional noise.
In particular, a large fraction of the misexpressed CGI- genes encode secreted proteins, many of which are associated with the senescence-associated secretory phenotype (SASP); aged kidneys and hearts from diversity outbred mice, mouse models with disrupted nuclear architectures, and progeria and senescent cells express proinflammatory secretory CGI- genes, and most proteins whose levels increase in aged plasma are encoded by CGI- genes. Together, our findings suggest that disorganization of the nuclear periphery in aged cells results in misexpression of CGI- genes that are a direct source of systemic inflammatory mediators associated with aging.