Fruit fly intestine may hold secret to the fountain of youth

The positive effect of calorie restriction on lifespan in many organisms is well established, but scientists are still working to understand the mechanism. The latest finding, in fruit flies, is that artificially increasing the number of mitochondria in the cells of the intestines – which happens naturally under conditions of calorie restriction – may be partially responsible for the effect.

Fruit fly intestine may hold secret to the fountain of youth

This chain of connections between the mitochondria and longevity inspired Jones and her colleague to investigate what happens when the PGC-1 gene is forced into overdrive. To do this, they used genetic engineering techniques to boost the activity of the fruit fly equivalent of the PGC-1 gene. The flies (known as Drosophila melanogaster) have a short lifespan, allowing the scientists to study aging and longevity in ways that aren’t as feasible in longer-lived organisms such as mice or human.

The researchers found that boosting the activity of dPGC-1, the fruit fly version of the gene, resulted in greater numbers of mitochondria and more energy-production in flies – the same phenomenon seen in organisms on calorie restricted diets. When the activity of the gene was accelerated in stem and progenitor cells of the intestine, which serve to replenish intestinal tissues, these cellular changes correspond with better health and longer lifespan. The flies lived between 20 and 50 percent longer, depending on the method and extent to which the activity of the gene was altered.

The research suggests that the mechanism by which health and longevity are increased involves greater robustness in the intestinal tissue as a result of having more mitochondria.

Modulation of Longevity and Tissue Homeostasis by the Drosophila PGC-1 Homolog

[W]e show that overexpression of the Drosophila PGC-1 homolog (dPGC-1/spargel) is sufficient to increase mitochondrial activity. Moreover, tissue-specific overexpression of dPGC-1 in stem and progenitor cells within the digestive tract extends life span. Long-lived flies overexpressing dPGC-1 display a delay in the onset of aging-related changes in the intestine, leading to improved tissue homeostasis in old flies. Together, these results demonstrate that dPGC-1 can slow aging both at the level of cellular changes in an individual tissue and also at the organismal level by extending life span. Our findings point to the possibility that alterations in PGC-1 activity in high-turnover tissues, such as the intestine, may be an important determinant of longevity in mammals.

Cell-Aging Hack Opens Longevity Research Frontier

This is pretty important, even though it’s only a proof of concept – not even a first step to developing a useful therapy for age-related health afflictions. What’s been done is to show that a state (senescence), which old cells reach when they near the limit of their useful lives, is not just a somewhat benign way of stopping the cell from becoming cancerous. Instead, senescent cells that aren’t eliminated naturally (by the immune system or by apoptosis) and remain in the body can degrade the health of the organism. Further, causing such cells to be eliminated is not only possible, but improves the organism’s overall health even though it does not lengthen lifespan. (And even this much has only been demonstrated in genetically altered mice, not humans.)

Cell-Aging Hack Opens Longevity Research Frontier

Research into longevity, that most fundamental and intractable of all human health challenges, moves slowly. It deserves to be described in terms of years, not individual studies. But once in a rare while, a finding has the potential to be a landmark.

Such is the case with a new experiment that flushed old, broken-down cells from the bodies of mice, slowing their descent into the infirmities of age.

The large caveats that inevitably apply to mouse studies still apply here, in spades. But even with those, the findings mark the first time that cellular senescence — its importance debated by biologists for decades — has been experimentally manipulated in an animal, demonstrating a fantastic new tool for studying its role in human aging.

The research involved a series of experiments, and if you’re up on your molecular biology, the details are interesting.

Worms with Genes for Long Life Pass on Longevity to Offspring…Even Without the Genes

Epigenetic changes in your parents’ chromosomes could affect your lifespan. At least, that is, if you’re a simple roundworm.

Recent research has shown that some epigenetic changes in plant DNA can be inherited. (See here, here). However, these changes aren’t robust, and tend to drop out after a few generations.

The epigenetic changes in plants that were heritable involved DNA methylation. The new research on roundworms (Caenorhabditis elegans) concerned a slightly different type of epigenetic change: methylation of a histone protein. Histones make up chromatin, the scaffolding around which DNA is wrapped around in chromosomes. There are four different histones, and two copies of each of these form a nucleosome. About 146 base pairs of DNA are wrapped around each nucleosome. The expression of genes whose DNA is wrapped around a nucleosome can be affected by the methylation state of the H3 histone.

Previous research had found that decreased levels of methylation of a specific part of the H3 histone resulted in longevity extensions of C. elegans by up to 30%. More specifically, a protein complex called H3K4me3 does the job of methylating the critical location in the H3 histone. Mutations of certain components of H3K4me3 were known to bring about the longevity extension effect.

How Longevity Is Passed On

Anne Brunet, an associate professor of genetics at the Stanford School of Medicine, found that mutations in a chromatin-modifying complex also significantly increased lifespan in C. elegans. The complex, known as the histone H3 lysine 4 trimethylation (H3K4me3) complex, is responsible for methylating a chromatin packaging protein called histone H3. This methylation is often associated with the increased expression of genes in the vicinity.

When Brunet and her colleagues knocked down members of the H3K4me3 complex—such as the WDR-5 and SET-2—they extended C. elegans life by up to 30 percent, suggesting that the epigenetic changes regulated by the complex controlled genes related to lifespan.

“Basically we think that the reason why those worms live longer is because they have less of this H3K4 mark at specific loci in the genome,” Brunet explained. “That probably results in changes in the expression of some genes,” such as those that regulate the aging process, she added.

That much was understood before the latest research. The new and rather surprising thing the new research has shown is that even if the mutations affecting H3K4me3 levels are eliminated in succeeding generations, the longevity extending effect persists for two more generations. The research found that expression of certain genes affecting metabolism – which often in turn affects longevity – persisted across generations, suggesting that other, as yet unknown, epigenetic changes occurred due to the original changes in H3 methylation.

The research paper itself concludes:

Our observations are consistent with the notion that H3K4me3 at specific loci may not be completely erased and replenished. Alternatively, the ASH-2/WDR-5/SET-2 complex could control the expression of the genes responsible for the erasure and replenishment of histone methylation marks between generations. Modulation of H3K4me3 modifiers in parents may also affect an unidentified protein or RNA that could in turn be inherited and cause lifespan changes.

Further reading:

Long life passed down through generations

Live long, pass it on

Worms with Genes for Long Life Pass on Longevity to Offspring…Even Without the Genes

Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans