Leaving a mark: New research shows how longevity is inherited across generations

(Press-News.org) New research in the roundworm C. elegans shows how changes in the parent’s lysosomes that promote longevity are transferred to its offspring. The work describes a new link between lysosomes—cellular organelles once thought to be the cell’s recycling center—and the epigenome—a set of chemical marks that modify gene expression. The study also details a new way that epigenetic information is transmitted from cells in the body to reproductive cells, allowing changes to be inherited without affecting the genetic code. These insights show how epigenetic modifications that help organisms cope with environmental stress can be conferred from parents to their offspring. In the Wang Lab, it’s not unusual for worms to live for a long time.

HHMI Janelia Research Campus Senior Group Leader Meng Wang and her team study longevity. They’ve shown that by overexpressing an enzyme in the lysosomes of the roundworm C. elegans, they can extend the worm’s life by up to 60 percent.    

But surprisingly, the team found the worms’ progeny without this genetic modification were still living longer than normal. When they crossed their long-lived worms with “wild-type” worms that weren’t overexpressing the enzyme—a routine lab procedure used to wipe clean any genetic manipulations—they saw that the offspring also lived longer than normal worms. Somehow, the longevity markers were being transferred from generation to generation, even four generations later.

In new research, Wang and her team uncover how changes in the worm’s lysosomes that promote longevity are transferred from cells in its body to its reproductive cells through histones—proteins that play a key role in organizing and regulating DNA. In reproductive cells, these histone messengers cause modifications in the worm’s epigenome—a collection of chemical tags that regulate gene expression—enabling the lysosomal changes to be passed from generation to generation without changing the underlying DNA.

The findings have repercussions well beyond longevity. Epigenetic modifications can help organisms cope with many different types of environmental stressors—from diet changes to pollutant exposure to psychological stress—and the new work shows how these advantages could be conferred from parents to their offspring.

“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 says. “It really provides a mechanism for understanding the transgenerational effect.”

Uncovering inheritance

The researchers found that one type of histone modification—a type of epigenetic change—was elevated in long-lived worms compared to those with normal lifespans. They wanted to see how this modification related to lysosomal changes that promote longevity.

Using a combination of genetic tools, transcriptomics, and imaging, they found that changes in lysosomal metabolism affecting the worms’ longevity activate a series of processes inside the cell. These actions trigger an increase in a specific histone variant, which is transported from the worm’s somatic or body tissues to its germline or reproductive cells through proteins that deliver nutrients to developing eggs. In the germline, the histone is modified, allowing the information from the lysosome to enter the germline and be passed from parent to child.

The researchers show that this pathway is activated during fasting, which causes a change in lysosomal metabolism—providing a link from the physiological phenomenon to the changes in the germline.

The new work adds to a growing body of evidence that lysosomes, once thought to only act as the cell’s recycling centers, also function as a signaling hub to control different processes in the cell and now are shown to affect generations.

The new research also unveils a new mechanism for transporting information from somatic to germline cells through histones, which could help explain how other types of inherited information are passed from parent to offspring.

By providing a mechanism for understanding how environmental changes to somatic cells are passed through the germline, the new work could help researchers better understand transgenerational effects that have been previously observed, like the malnutrition of a parent affecting its offspring.

“We now show that the soma and the germline can be connected by the histone and can carry memorable genetic information for generations,” Wang says.

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