Scientists studying tiny nematodes have discovered how the secrets of a long life can be passed from parents to their offspring – without altering the DNA. The discovery shows that when certain cell structures, called lysosomes, change in a way that promotes longevity, these benefits can be transferred from the body cells to the reproductive cells. This information is carried by histones, special proteins that help organize DNA and allow the “memory” of these changes to be inherited.
How Changes in the Worm’s Lysosomes that Promote Longevity are Transferred to Reproductive Cells
In the Wang lab, it is not uncommon for worms to live long lives. Meng Wang, Senior Group Leader at the HHMI Janelia Research Campus, and her team are researching longevity. They have shown that by overexpressing an enzyme in the lysosomes of the nematode C. elegans, they can extend the worm’s lifespan by up to 60 percent. Surprisingly, however, the team found that even the offspring of the worms without this genetic modification lived longer than normal. When they crossed their long-lived worms with “wild-type” worms that did not overexpress the enzyme – a routine laboratory procedure to eliminate genetic manipulations – they found that the offspring also lived longer than normal worms. Somehow, the longevity markers were passed from generation to generation, even four generations later.
In the new study, Wang and her team reveal how changes in the worm’s lysosomes that promote longevity are transferred from the cells of its body to its reproductive cells via histones – proteins that play a key role in organizing and regulating DNA. In the reproductive cells, these histone messengers cause changes in the worm’s epigenome – a collection of chemical markers that regulate gene expression – allowing the lysosomal changes to be passed from generation to generation without altering the underlying DNA. The results have implications that go far beyond longevity. Epigenetic changes can help organisms cope with many different types of environmental stressors – from dietary changes to pollutants to psychological stress – and the new work shows how these benefits can be passed from parents to their offspring. “Inheritance is always thought to occur in the nucleus, but now we show that histones can migrate from one place to another, and if these histones have modifications, it means that epigenetic information is transferred from one cell to another,” says Wang. “This provides a mechanism for understanding the transgenerational effect.”
The Discovery of Inheritance
The researchers found that one type of histone modification – a type of epigenetic modification – was increased in long-lived worms compared to worms with normal lifespans. They wanted to find out how this modification was related to lysosomal changes that promote longevity. Using a combination of genetic tools, transcriptomics and imaging, they found that changes in lysosomal metabolism that affect worm longevity activate a number of processes within the cell. These processes trigger an increase in a specific histone variant, which passes from the worm’s somatic or body tissue into its germline or reproductive cells via proteins that transport nutrients to the developing oocytes. In the germline, the histone is modified so that the information from the lysosome enters the germline and can be passed on from parent to child.
The researchers show that this pathway is activated during fasting, leading to a change in lysosomal metabolism – thus establishing a link between the physiological phenomenon and the changes in the germline. The new work adds to a growing body of evidence that lysosomes, previously thought to function only as recycling centers of the cell, also serve as signaling centers to control various processes in the cell and have now been shown to influence generations. The new research also reveals a new mechanism for the transport of information from somatic to germline cells via histones, which could help explain how other types of inherited information are passed from parents to offspring. By providing a mechanism for understanding how environmental changes are passed on to somatic cells via the germline, the new work could help researchers better understand previously observed transgenerational effects, such as malnutrition of a parent affecting its offspring.