How Longevity May Be Inherited Across Generations

For years, scientists have studied why some organisms live longer than others. While genes play an important role in aging, research continues to show that lifespan is not determined by DNA sequence alone. The way genes are regulated, through epigenetic marks that help turn genes on or off, may also influence how organisms age and, in some cases, how certain biological effects are passed to future generations.

A study from researchers at Howard Hughes Medical Institute’s Janelia Research Campus adds another layer to this idea. Using the roundworm Caenorhabditis elegans, Meng Wang, a Senior Group Leader at Janelia, and her team found that changes linked to longevity can be passed from parents to offspring through an epigenetic pathway involving lysosomes, histones, and reproductive cells.

The finding is surprising because lysosomes are often thought of as the cell’s recycling centers. They break down and reuse cellular materials, helping cells remove waste and maintain balance. But scientists now recognize that lysosomes do more than clean up cellular debris. They can also act as signaling hubs that help cells respond to metabolism, stress, and changing environmental conditions.

In previous articles, we have discussed how cellular cleanup systems such as autophagy and fasting or reduced nutrient intake may be tied to aging through epigenetic mechanisms. The Janelia study builds on these ideas by showing that lysosomal activity may not only affect the lifespan of an individual worm but may also send information to the next generation.

Wang’s earlier work showed that increasing the activity of an enzyme in the lysosomes of C. elegans could extend the worms’ lifespan by as much as 60 percent. But when the researchers crossed these long-lived worms with normal worms, something unexpected happened. The offspring no longer carried the original genetic modification, yet they still lived longer than normal worms. Even more surprising, this longevity effect could be seen for several generations.

That raised an important question: if the original DNA change was gone, how was the longevity effect being inherited?

The answer appears to involve a lysosome-to-epigenome signaling pathway. In simple terms, changes in lysosomal metabolism created a signal that eventually reached the germline, the reproductive cells that give rise to the next generation. The researchers found that lysosomal activity increased levels of a histone variant called H3.3, which was then transported from the worm’s body cells to its germline. Once there, H3.3 was associated with H3K79 methylation, a chemical modification on histone H3 that can help regulate gene activity.

Rather than passing on a new DNA sequence, the worms appeared to pass on regulatory information through histones and histone methylation. Histones help package DNA inside the nucleus, but they also carry chemical marks that influence how genes are used. In this study, H3.3 seemed to help move the signal from body tissues to reproductive cells, while H3K79 methylation helped preserve the longevity-related message in the germline.

As Wang explained, “It really provides a mechanism for understanding the transgenerational effect.” That mechanism is important because it helps answer a long-standing question in epigenetics: how can information from the body’s cells reach reproductive cells and influence offspring without altering the DNA code itself?

Research on histone modifications and aging has shown that these marks can shape how genes are regulated over time. These findings expand on that concept by suggesting that histones may do more than regulate gene activity within a single cell. They may also help carry biological information between tissues and across generations.

The researchers found that this pathway involved several key signals tied to lysosomes, metabolism, and chromatin regulation. Changes in lysosomal activity affected nutrient-sensing pathways such as AMPK and mTOR, which are already known to play roles in aging. These shifts were linked to increased H3.3 and higher levels of H3K79 methylation, helping connect lysosomal metabolism to inherited longevity.

Fasting also appeared to activate the same pathway. Since fasting changes lysosomal metabolism, the finding suggests that nutrient conditions may influence not only how an organism ages, but also how certain epigenetic signals are passed to future generations.

The researchers caution that this does not mean lifespan is simply inherited from parent to child, especially in humans. C. elegans is a useful model for studying aging, but findings in worms need more research before they can be applied to mammals. Still, the study offers an important clue about how epigenetic information may move across generations.

Taken together, the findings add to the idea that aging is shaped not only by genes, but also by how those genes are regulated. In this case, lysosomes sensed metabolic changes, histones helped carry the signal, and the germline received an epigenetic message that affected future generations.

Source:Qinghao Zhang, Weiwei Dang, Meng C. Wang. Lysosomes signal through the epigenome to regulate longevity across generations. Science, September 25, 2025.
 
 Resource:Howard Hughes Medical Institute. Leaving a mark: New research shows how longevity is inherited across generations. September 25, 2025.