Name: Noah Kurland Author/Year: Cesar L. Moreno and Charles V. Mobbs- 11-13-2016
Broad Topic: The epigenetic components of aging.
Specific Topic: The age related effects of dietary restriction.
What is known:
.The process propelling aging has been proposed: Changes in gene expression, perhaps due to genomic instability, genetic damage, destroyed nutrient sensing, and finally epigenetic mechanisms such as DNA methylation.
.It has been discovered that attacking epigenetic mechanisms can actually act as a therapy to try to postpone or inhibit age related deficits.
.Intervening using techniques such as dietary restriction may offer promising results, as they may act utilizing epigenetic refinements.
“The goal of DR research is to determine mechanisms mediating these protective effects, and activate these mechanisms pharmacologically or by some other means” (Moreno).
Experimental Question: What drives the aging process, and what links age to disease? More specifically, how is the aging process as well as age-related diseases regulated by epigenetic mechanisms, and how can dieting be mediated by this epigenetic machinery?
Figure 1: “Aging influences global epigenetic characteristics”
Technique: The authors address the general characteristics of epigenetics and delve into the specific components that are affected by aging. They also introduce a few studies to validate their affirmations.
Aging can influence the genomic environment through…
Changes to nuclear lamina, telomere shortening, DNA methylation, and chromatin modifications.
Changes to nuclear lamina- mutations in A-type result in progeroid syndromes like Hutchinson-Gilford.
Telomere shortening- impedes the replicative potential in mitotic-non cancerous cells. Accelerated aging can be shown through these inactivating mutations.
The authors use a mice study to explain the potential negative effects of reducing telomere length- it results in progeroid syndromes, while “intervening in these models by reactivating telomerase can reverse neurodegeneration”. Dietary restriction helps maintain telomere length- will talk about below.
DNA methylation- The authors talk about early studies that suggested global DNA methylation decreases with age, but that recent studies have depicted intricate patterns of methylation where DNA methylation is positively correlated with age.
It is talked about that most likely, DR influences methylation in the epigenome. The authors use examples of studies that show hypoglycemia and exercise increase adenosine in brain tissue, which has been revealed to reduce DNA methylation. Additionally, ketogenic diets have also been shown to do the same thing.
It is talked about how targeting certain changes among chromatin can protect against disease. Specifically, in a study with 11 individuals between the years of 0.5 to 69 years of age, H3K4 tri-methylation was reported to increase with age, so preventing this methylation would increase lifespan; however, H3K27 trimethylation was found to decrease with age. But these effects are dependent on the same signaling pathways- specifically, the IGF-1 signaling pathways. It was found that among rats, H4K20 tri-methylation also increased with age.
This data demonstrates the actual alterations on an epigenetic scale that result because of aging. It provides the basic knowledge to understand what will be talked about throughout the remainder of the article. It also supports that fact that there are common demethylation targets which respond to multiple types of dieting.
Figure 2: Evidence that protective mechanisms of DR are hierarchical via nutrient-sensing neurons
Technique: Studies show that protective effects of DR are seen across all animal phyla; moreover, these shared mechanisms include improved insulin sensitivity, decreased body temperature and changes in circadian rhythms, reduced GH/IGF-1 signaling, and reduced glucose metabolism. To support the idea that nutrient sensing neurons could potentially regulate protective effects of Dietary Restriction, studies in C. elegans are introduced. These studies show that DR is only dependent on two nutrient sensing ASI neurons in order to increase lifespan. Additionally, in flies the neurosecretory cells that respond to nutritional state by releasing peptides similar to insulin also have the ability to tap into the protective impacts of DR and ultimately increase lifespan. In mice, particularly in the hypothalamus region, it has been talked about that reduction of NF-kB signaling increases lifespan as well, but impairments in this nutrient signaling can lead to things like obesity and diabetes. The study is further analyzed, as the authors describe how the knockout of a particular protein (Creb-binding protein) can disrupt nutrient signaling, resulting in obesity, and lowered energy rate.
These studies/ this data supports the notion that neurons which are nutrient sensing especially in the hypothalamus can modulate the aging process and associated diseases; furthermore these studies illustrate how the epigenome of these nutrient sensing neurons is vital for maintaining homeostasis.
Figure 3: Evidence that epigenetic changes mediate protective effects of dietary restriction
Technique: Studies are presented, all indicating the relationship between epigenetic mechanisms and lifespan. A yeast study showed a longer life can be driven by the increased expression of the Sir2 gene, which exhibits HDAC activity. There were similar reports regarding studies on flies and C.elegans. There were then studies to replicate these results and dive into more detail. It was found that Sir2 HDAC activity was in fact enhanced by NAD+ levels and that mutations in Sir2 prevent the beneficial and protective effects of DR.
Other studies have utilized the mammalian sirtuin, Sirt1 to see its relationship to metabolic functions produced by DR. It was found that particularly in the hypothalamus, overexpression of Sirt1 lengthens the lifespan of mice, and “ubiquitously enhanced expression of Sirt6 was shown to increase lifespan in male mice” while low levels of this Sirt6 resulted in shorter lifespans. Protective effects of DR have to do with mitochondrial Sirt3 like age related hearing loss and modulation of proteins within the mitochondria. A recent report supports the role for Sirt1 in mammalian lifespan by indicating that the NAD+ precursor nicotinamide riboside, dependent on Sirt1, increases lifespan.
These observations substantiate the sirtuin’s playing a role in mediating protective effects of DR, but the question still remains of how they advance these protective effects.
Other studies are put forth, illustrating the CREB-binding protein (Cbp) and its effect on increasing lifespan and regulating the protective effects of dietary restriction. Across numerous strains of mice, it was seen that the expression of hypothalamic Cbp predicted over 80 percent of lifespan discrepancy, meaning it plays huge role in lifespan. It was also found that inhibition of the miRNA-80 promotes lifespan through Cbp, but that inhibition of similar cbp prevented the “life extending” effects of Daf-2, an insulin receptor like mutation. Studies also suggest that Cbp is tied to HAT activity and promotes metabolic responses familiar to DR. An example that’s given is that when Cbp interacts with Ppar–γ and Ppar-α, genes are induced that promote lipid metabolic function and obstruct the glucose metabolism; moreover, Cbp responds to low blood sugar by increasing “hepatic glucose output.” It was also reported in the article that when mice fasted hypothalamic Cbp expression was increased.
These observations emphasize that Dietary restriction and and the insulin receptor-like pathways share similarities regarding the role and activity of Cbp.
Figure 4: Epigenetic mechanisms engaged by DR and other ketogenic diets
Technique: The authors once again use a variety of studies to explain how dietary restrictions affect the epigenetic mechanisms. First, the effects of fasting and dietary restriction on blood chemistry is looked at. It is elucidated that the elevation of ketone bodies, specifically β-hydroxybutyrate can arise due to fasting or DR. These bodies essentially make up the process of Ketogenesis which occurs in the liver mostly and are fueled by free fatty acids as a result of lowered insulin because of fasting. It is explained that these diets were developed based on the effects of fasting in order to negate the symptoms of epilepsy. More studies to suggest the protective effects of DR focus on its ability to reduce glucose metabolism and aid the use of different substrates. It was observed among mice that 3-OHB was able to block glucose from affecting the hypothalamus and its corresponding gene expression.
These observations lead to more observations and the conclusion that a KD without caloric restriction enables the reversal of diabetic kidney failure in mice. The production of 3-OHB therefore, can be attributed to mediating the effects of KD and DR.
Other studies- among C. Elegans and mice demonstrate that there are HDAC inhibitors (butyrate and phenylbutyrate) that actually mimic protective effects of DR. This shows that 3-OHB is also an HDAC inhibitor. Furthermore, increased acetylation from DR come with protective genes such as Foxo3a. The authors make note that this concept is supported by the observation that intermittent DR, not reducing the total caloric intake, but resulting in more production of ketone bodies, basically reversing the pathology of huntington’s disease, as striatal HDAC2 is reduced significantly. Lastly, other mouse models of neurodegeneration are seen to be impacted by these neuroprotective effects. The HDAC inhibitor improves deficits pertaining to neurocognition and the sodium butyrate improves memory.
These observations question whether changes among gene expression in places similar the hypothalamus, stem from similar epigenetics. To support this idea, the authors include a graph that displays the ketogenic diet and the DR, both increasing the 3-OHB and producing alike hypothalamic outlines of gene, having to do with the intermediate metabolism.