The structure of the cell nucleus is determined by the nuclear lamina, protein filaments that support the nuclear membrane and anchor the important components within the nucleus. Correct function of the lamina and its component parts are required in order for the cell to carry out vital functions such as nuclear DNA maintenance and repair, gene expression, and cell replication. In a cell with faulty nuclear lamina, the nucleus is misshapen and all these processes run awry. Such cells tend to become senescent in response to internal dysfunction, and cause damage to surrounding tissue via their inflammatory secretions if they are not then destroyed promptly by the immune system. Internal self-destruction mechanisms exist, but problems with gene expression may cause them to fail.
Regular readers will recall that this is the scenario in progeria, a condition with the appearance of accelerated aging. Progeria is caused by mutation in the lamin A gene that codes for a protein that is an important component the nuclear lamina. Progeria patients have dysfunctional, broken cells with misshapen cell nuclei, and as a consequence they die young of cardiovascular disease that is very similar to the conditions such atherosclerosis that normally only affect much older individuals. Researchers have found that lamin A is broken in small amounts over the course of normal aging, with damaging results, but it is an open question as to whether that is significant in comparison to the other causes of aging.
In the research noted here, a more subtle age-related disruption to the nuclear lamina is examined, connected to the behavior of FOXA2 and lamin B1. The researchers focus on liver tissue, and suggest that problems with nuclei in the aged liver cause sufficient change in gene expression to contribute to organ dysfunction and age-related disease. The mechanism seems plausible, but the question as before is the degree to which it occurs, and whether it is possible to definitively tie it to systematic changes in gene expression that are broadly similar in all individuals. That last point seems at least at first a challenge; one might expect problems with nuclear structure to have more random effects on the capacity of a cell to carry out its operations. Nonetheless, it is interesting work and worth a look in the broader context of whether or not the structure of the nucleus is a major, minor, or insignificant process in normal aging.
A new finding suggests that fatty liver disease and other unwanted effects of aging may be the result of our cells' nuclei - the compartment containing our DNA - getting wrinkly. Those wrinkles appear to prevent our genes from functioning properly. The location of our DNA inside the cell's nucleus is critically important. Genes that are turned off are shoved up against the nuclear membrane, which encases the nucleus. But with age, our nuclear membranes become lumpy and irregular, and that prevents genes from turning off appropriately.
Looking at a model of fatty liver disease, researchers found that our livers become studded with fat as we age because of the wrinkly nuclear membranes. "When your nuclear membrane is no longer functioning properly, it can release the DNA that's supposed to be turned off. So then your little liver cell becomes a little fat cell." The accumulation of fat inside the liver can cause serious health effects, increasing the risk of type 2 diabetes and cardiovascular disease, even potentially leading to death. The membrane wrinkling stems from a lack of a substance called lamin, a cellular protein that comes in various forms. By putting the appropriate lamin back, we might smooth out the membrane.
Researchers suspect the wrinkling of the nuclear membrane is responsible for unwanted effects of aging in other parts of the body as well. "Every time I give this talk to colleagues, they say, 'Well, do you think this is a universal mechanism?' In my opinion, I think it is."
Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors.
We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de-repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.