Shawn Ahmed, an associate professor of genetics at the University of North Carolina School of Medicine, Chapel HillAging is experienced by all of life on Earth. But studying the aging process is usually limited to the study of a single organism’s lifespan. So what we currently know about aging is not highly specific; our cells divide many times throughout our lives and eventually cause organs and our bodies to age, break down and fail.

New research, however, suggests that how we age might depend on cellular interactions that we inherit from our ancestors, accumulating throughout many generations. The work could lead to a deeper understanding of factors that govern aging and age-related diseases.

By studying the reproductive cells of nematodes—tiny worms found in soils and compost bins—Shawn Ahmed, an associate professor of genetics at the University of North Carolina School of Medicine, Chapel Hill, has identified a genome silencing pathway and a genome signaling pathway that could play a role in the aging process.

Ahmed and his colleagues have shown that tweaking specific cellular mechanisms helps the tiny worms overcome infertility through a pathway of cellular interactions that result in long life. The work provides clues as to how molecular interactions in cells of one organism affect progeny many generations later.

Specifically, Ahmed and his team identified a Piwi/piRNA genome-silencing pathway, the loss of which results in infertility after many generations. They also found a signaling pathway—a series of molecular interactions inside cells—that they could tweak to overcome infertility while also causing the worms to live longer adult lives.

The research, which was done with scientists at the University of Cambridge, suggests that it’s possible to manipulate the aging process of progeny before they’re even born. The finding gives scientists a deeper understanding of what may govern aging and age-related diseases, such as some cancers and neurodegenerative conditions.

The team reported their work in the May 8, 2014 issue of Cell Reports.

“We revealed an unexpected link between a major pathway that regulates aging in post-mitotic cells, the insulin signaling pathway, and the piRNA pathway that promotes genome silencing and transgenerational fertility in germ cells,” Ahmed said. “This work implies that transgenerational fertility defects could correspond to a form of 'proliferative aging,’ or aging of cells as they divide. This sort of aging occurs in many types of human somatic stem cells, but how this is regulated is not entirely clear, and it was unexpected that a somatic stress response pathway could strongly suppress what we view as a form of ‘heritable stress’ in germ cells.”

Typically, nematodes produce about 30 generations in a matter of months and remain fertile indefinitely. Ahmed and colleagues found that a mutation in the Piwi/piRNA cellular pathway of germ cells gradually decreased the worms’ ability to reproduce as the mutation was passed down through the generations and eventually caused complete sterility.

But when Ahmed’s team manipulated a different protein—DAF-16/FOXO—the nematodes overcame the loss of the Piwi pathway. The worms did not become sterile; generations of worms reproduced indefinitely, achieving a sort of generational immortality. Moreover, it has been well established that DAF-16/FOXO plays a role in nematodes living longer.

Achieving longer life suggests that there’s an effect on the aging of somatic cells—the cells that make up the body and organs of an organism.

“We were surprised by the discovery, which was initially based on observations that brief periods of starvation could benefit the fertility of mutants that are defects for the piRNA pathway,” Ahmed said. “This is the first time that piRNAs, which primarily silence repetitive segments of the genome in germ cells, might be relevant to the aging process.”

“The transgenerational fertility defect of piRNA mutants take many generations to accrue. The germ cells of such mutants divide many times in this context but then become completely sterile,” he explained. “This defect could therefore reflect a transgenerational germ cell proliferation defect that might be related to aging, or it could reflect a process that is specific to germ cells. Our demonstration that a somatic aging pathway can suppress the fertility defect of piRNA mutants suggests that we might be working on a process that is related to aging in somatic cells.”

“That’sthe really interesting thing about this,” added Ahmed, who has worked on this project for the past 15 years since he completed his Ph.D. work. “What we’ve found implies that there’s some sort of relationship between somatic cell aging and this germ line immortality process we’ve been studying.”

What that relationship is, precisely, remains unknown. But so does the exact mechanism by which human somatic cells age as they divide throughout our lives. That is, exactly how we age—at the cellular level—is still not entirely understood.

“It will take so me time before we understand how this might be applied to humans,” he added. “We have barely scratched the surface in worms.”