Lysosomes are thought of as cellular organelles that play an important role in recycling proteins and maintaning cells by breaking down stuff that isn’t needed. But new research has found that lysosomes can also have a role in regulating longevity. This work used a common research model known as Caenorhabditis elegans, a nematode worm. The investigators found that when they expressed high levels of a particular enzyme in the worms’ lysosomes, their lifespan increased as much as 60%. Not only did the modified worms live longer, but their offspring also lived unusually long lives. The findings have been reported in Science.
The long-lived worm offspring did not carry the same genetic modification as their long-lived parents. And when these offspring were mated with unmodified worms that also expressed normal enzyme levels, lengthier-than-usual lifespans still persisted. As many as four generations continued to live longer than usual.
This study has shown that the worms' lysosomes were changed to promote longevity, and these changes moved into reproductive cells through proteins known as histones. Histones are critical to DNA organization, and they are part of the epigenome–features or changes in which gene expression can be altered without affecting the sequence of DNA. These might include alterations to DNA and structure or organization, or chemical groups that tag DNA.
Longevity seems to be heritable through a specific type of histone modification that was identified in this study. This histone modification was more common in worms that lived longer lifespans. Additional work revealed that shifts in lysosomal metabolism were triggering processes that led to an increase in this histone modification. This modification was then transferred to the reproductive cells of the worms, allowing it to be passed down through the germline from parents to offspring.
In humans, the epigenome might be affected by many things including environmental pollutants, diet, or stress, for some examples. The study showed that the same histone modification-increasing pathway was also triggered by fasting, since fasting leads to changes in lysosomal metabolism.
"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," explained HHMI Janelia Research Campus Senior Group Leader Meng Wang. "It really provides a mechanism for understanding the transgenerational effect."
This research has added to growing evidence that lysosomes are more than just recycling centers. It has also revealed a novel mechanism in which environmental factors in parents could be affecting offspring.
Sources: HHMI Janelia Research Campus, Science