New research in C. elegans from scientists at Howard Hughes Medical Institute (HHMI) helps explain how changes in the parents’ lysosomes that promote longevity are transferred to their offspring. Their findings are detailed in a new Science paper titled “Lysosomes signal through the epigenome to regulate longevity across generations.”
The work comes out of the laboratory of Meng Wang, PhD, a senior group leader at HHMI’s Janelia Research Campus. Previous research from the Wang lab showed that overexpressing a particular enzyme in C. elegans lysosomes extended its life by up to 60 percent. Surprisingly, offspring from these worms that did not have the genetic modification as their parents also lived longer than normal. And when these long-lived worms were crossed with wild-type worms that did not have the same modification, offspring from those unions also lived longer.
Based on these findings, the researchers hypothesized that the longevity markers were somehow being transferred across generations. Their latest study in Science sheds some light on how this might be happening. According to the paper, Wang and her team found that the changes in C. elegans lysosomes are transferred to its reproductive cells via histones. In reproductive cells, these histone messengers modify the worm’s epigenome, enabling the lysosomal changes to be passed through the generations without changing the underlying DNA.
“You always think that your inheritance is in the nucleus, within the cell, but now we show that the histone can go from one place to another place, and if that histone carries any modification, that means you are going to transfer the epigenetic information from one cell to another,” Wang said. “It really provides a mechanism for understanding the transgenerational effect.”
Specifically, the scientists identified a specific histone modification was elevated in the worms that lived longer compared to those with normal lifespans. Then using a combination of tools including transcriptomics and imaging, they found that changes in lysosomal metabolism, which are activated during fasting, kick off a series of processes in the cells which triggers an increase in a specific histone variant. That histone is then transported to the reproductive cells via proteins, where it is modified in a way that allows the lysosomal information to enter the germline where it can be transferred from parent to offspring.
Besides conferring longevity across generations, the team believes that this mechanism could help explain how other types of inherited information is passed from parent to offspring in C. elegans. For example, the findings could help researchers better understand previously observed transgenerational effects like the malnutrition of a parent affecting its offspring, or how epigenetic modifications for coping with environmental stress can be passed from parents to offspring.
