This article on dietary restriction is part of a longer series covering all things aging and longevity. Other articles in the series have touched on cell senescence, bone and muscle maintenance, heart health, DNA damage, and a number of other topics.
“You are what you eat”, so the saying goes. But how much you eat may be just as important. In recent years, dietary restriction has been shown to extend lifespan and improve health — at least, in mice and fruit flies. Dietary restriction has also been linked to slowed brain aging, delaying the onset of cognitive decline. The exact mechanisms by which it does this, however, have remained elusive. Now, researchers at the Buck Institute for Research on Aging may have uncovered a key part of the puzzle. Their findings, published in Nature Communications, suggest that the brain benefits associated with dietary restriction can be traced to a gene called oxidation resistance 1 (OXR1), which helps protect cells from oxidative damage.
Locating Longevity Genes
Fruit flies, with their short lifespan of 40 to 50 days, are ideal for studying longevity. Researchers can quickly observe the effects of environmental or genetic factors, such as diet, on aging and lifespan. To facilitate this work, scientists have developed the Drosophila Genetic Reference Panel (DGRP), a collection of around 200 “standardized” fruit fly lineages.
In this study, the team from the Buck Institute made use of 160 strains from the reference panel. Each strain was split into two groups: one that was allowed to eat as much as they pleased, known as ad libitum in the technical lingo, and another that received only a tenth of their usual diet. After the fruit flies had undergone their full life cycles, their genomes were scanned.
The researchers homed in on variants of five genes that were strongly correlated with extreme longevity. Two of the genes are known to have corresponding versions in humans: ferredoxin (Fdxh) and mustard (mtd). The human versions of these genes are ferredoxin 2 and Oxidation Resistance 1 (OXR1), respectively. They would have evolved from a common ancestor a long time ago and continue to serve a similar function across species.
Of these, mustard/OXR1 caught the researchers’ attention. Humans who lack the oxidation resistance 1 gene suffer from severe defects in the central nervous system and the brain. They are also prone to premature death. Whereas, in mouse models, artificially over-activating the gene protects against amyotrophic lateral sclerosis (ALS), a disease affecting motor neurons of the spinal cord, which causes progressive weakness and breakdown of muscles.
OXR1 and Brain Health
Depending on the situation, genes can be turned “on” or “off”. This process, known as gene expression, determines when and where proteins and messenger RNA (mRNA) are made; genes, after all, provide the genetic instructions for the production of proteins. Regulation of gene expression also acts as a kind of “volume control” by shaping how much of a protein is made. When genes are highly expressed —in the “on” position— they are said to be upregulated or overexpressed. When their expression is reduced —the “off” position— they are downregulated or underexpressed.
Analysis of the fruit fly genomes showed that dietary restriction triggered a sevenfold increase in the expression of mustard mRNA in the brains of the fruit flies. These were the same fruit flies that exhibited an increased life span. Blocking the expression of the mustard gene, on the other hand, caused serious developmental defects and curtailed life span, regardless of the diet the mice followed. This suggests that mustard is integral to longevity.
Similar results were observed when analyzing human neurons for expression of oxidation resistance 1 and life span.
But how is it that the mustard/oxidation resistance 1 genes are having this impact on longevity and brain health? The researchers discovered that it may come down to a process known as endosomal protein recycling. In brief, this is a kind of cellular waste management system: when things are internalized by a cell, they have to be sorted through and separated into a “trash” pile, which will be destroyed, or a “recycling” pile, which will be returned to the cell membrane for reuse.
A key player in endosomal recycling is a multi-protein complex called the retromer. This protein complex is preserved across all eukaryotes — basically, all animals, plants, and fungi. Dysfunction of the retromer causes lysosomes, the cellular “incinerators”, to go haywire, interrupting the removal of cellular trash and causing it to pile up. Mutations of the retromer have been associated with Alzheimer’s and Parkinson’s diseases.
Through their genetic analyses and experiments, the researchers concluded that mustard/oxidation resistance 1 interact with and maintain the retromer complex, helping to stave off any neurodegenerative complications associated with its dysfunction. This was confirmed by the fact that artificial stabilization of the retromer complex manages to rescue cognitive and longevity defects induced by mustard/oxidation resistance 1 deficiency. By boosting the expression of these genes, dietary restriction encourages good brain health.
Caveats
Although exciting, this work comes with a number of caveats. These are the same caveats that much of the research on dietary restriction faces.
The first thing to consider is that fruit flies are very different from us humans. That’s exactly what makes them such a convenient resource for studying longevity. They are small, relatively simple, and short-lived; we are relatively large, complex, and long-lived. This makes it tricky to extend conclusions drawn from research on fruit flies to humans. The same goes for research in mice. In fact, animal research as a whole isn’t always a good predictor of human outcomes. The closer the animal is to humans, the more transferable the results — think research on apes and monkeys. But the closer the animals are to humans, the more difficult it is to study longevity because their natural life spans are longer as well.
Another issue in many of these studies, including the one discussed here, lies at the level of methodology. Often, the animals not subjected to dietary restrictions are allowed to eat as much as they want. Think of the Latin term used above, ad libitum or “to one’s pleasure”. This risks skewing the results, since the difference in life span between the diet group and the ad libitum group may be down to poor overall health in the group allowed to gorge itself.
On a broader note, the effects of dietary restriction in humans will be difficult to test. Again, we live long lives, so it will take a while for results to be available. Even then, there are so many factors that impact longevity that it becomes difficult to isolate just one. Finally, it is unlikely that humans can be kept to the same standards of caloric restriction as other animals: good luck convincing someone to eat only 10% of their usual intake for the bulk of their life.
Implications & Takeaways
Keeping in mind that the findings of this latest study need to be taken with a grain of salt, they still offer valuable insights into a possible mechanism regulating brain health and aging. According to the researchers, dietary restriction increases the expression of mustard/oxidation resistance 1 genes which, in turn, help maintain retromer function in neurons. This staves off cognitive decline and helps decrease the risk of neurodegenerative disorders.
This information may be helpful down the road in developing pharmaceuticals that activate oxidation resistance 1 expression independently of caloric intake. By cutting out the middleman, we would be left with the best of both worlds: all the benefits of dietary restriction with none of the frustrations.
