The longstanding biological puzzle of why women generally outlive men may be nearing a solution: scientists have identified a potential link between sex cells (sperm and egg) and lifespan.

Scientists in Japan showed for the first time in vertebrates that cells that develop into eggs and sperm can drive sex differences in lifespan. Removing these cells leads to animals with the same life expectancy.

What a little fish with a short life can teach us about bridging the lifespan gap

Germ cells, which give rise to eggs and sperm, play crucial roles beyond reproduction. These cells develop in the ovaries and testes in humans. Previous studies in invertebrates like C. elegans and Drosophila have shown that germ cell removal can extend lifespan and affect growth. However, the impact of germ cells on somatic growth and aging in vertebrates remained unclear.

The new experiments were conducted on turquoise killifish (Nothobranchius furzeri). These freshwater fish mature sexually within a fortnight and live for only a few months — it’s the shortest lifespan of any vertebrate. This very short life cycle makes these animals ideal for a study aiming to assess how various factors affect lifespan. By targeting genes essential to germ cell survival, researchers were able to produce germ-cell-removed animals.

The study found that removing germ cells affected the lifespan of male and female killifish differently. In females, germ cell removal decreased lifespan by about 10%, whereas in males, it increased lifespan by 13%. This difference is linked to changes in hormonal pathways and was very surprising — the researchers expected an enhanced lifespan across the board. Ultimately, the lifespan gap between males and females was equalized.

Hormones and killifish lifespan

“After removing the germ cells, male killifish lived longer than usual and female lifespans became shorter,” explains lead author Kota Abe of Osaka University. “We wanted to understand how germ cells could affect males and females so differently. Our next step was to investigate the factors responsible.”

Both sexes showed increased body size after germ cell removal, but the underlying mechanisms differed. In females, the increase was associated with elevated insulin-like growth factor 1 (IGF-1) signaling, while in males, it was linked to enhanced vitamin D signaling.

In females, reduced estrogen levels following germ cell removal led to increased cellular stress and signs of accelerated aging. Conversely, males exhibited improved muscle regeneration, skin health, and bone density, likely due to enhanced vitamin D signaling. This suggests that germ cells play a protective role in maintaining somatic health, with distinct effects based on sex.

The intriguing link between vitamin D and enhanced lifespan

The vitamin D association was particularly intriguing and prompted the researchers to investigate it further. When the team supplemented killifish with vitamin D, they observed lifespan increases of 21% in males and 7% in females. While no adverse effects were noted, the authors emphasized the importance of using appropriate amounts of vitamin D. Typically, guidelines recommend a daily supplement of 10 micrograms (400 IU vitamin D) during autumn and winter, cautioning against daily doses exceeding 100 micrograms.

“When we administered active vitamin D, we found that the lifespans of both males and females were significantly extended, suggesting that vitamin D signaling provides health benefits throughout the body,” explains senior author Tohru Ishitani. “Our work suggests that vitamin D signaling could influence the longevity of other vertebrates, including humans.”

These findings offer new insights into the trade-offs between reproduction, growth, and aging. In evolutionary biology, it’s well understood that reproduction can come at a cost to somatic maintenance. This study supports this theory by showing how germ cells, through different hormonal pathways, balance growth and aging differently in males and females.

More questions to answer

Females tend to live longer than males across many vertebrate species. For instance, female apes and old-world monkeys typically outlive their male counterparts. Humans are no exception. Globally, women live about 5% longer than men on average. Numerous factors contribute to this disparity, including higher accident and suicide rates among young men and generally healthier lifestyles among women. However, environmental and lifestyle factors alone do not always account for the lifespan gap. And this is where these exciting new findings may come in.

The question of whether sperm production suppresses men’s life expectancy remains open. However, there are now good reasons to believe that simply being born biologically male inherently comes with a shorter lifespan. Previously, a 2012 study of Korean eunuchs found castrated men lived 14 to 19 years longer than non-castrated men. However, other factors from these historical records, dating from the 16th to the 19th century, complicate things so it’s difficult to draw precise conclusions.

Further research is needed to explore these mechanisms in other vertebrate models and eventually in humans. Understanding how germ cells communicate with somatic tissues to regulate growth and aging could pave the way for novel treatments that enhance healthspan and lifespan.

The findings appeared in the journal Science Advances.