By Tiffany Chen

From pilot whales hunting squid in the ocean to domestic cats chasing lasers across the hallway, most females live longer than males in the animal kingdom. This is especially true in humans. Despite differences across culture and environment, there is near unanimity of data supporting female longevity superiority, and scientists want to know why.

Researchers from Belgium revealed that females might possess longevity superiority through gender-specific responses to GIT2, a keystone protein that may act as a controller of aging networks, in the hypothalamus. The study published in the journal Mechanisms of Ageing and Development, December 2019, reveals that females demonstrate greater resilience to pro-aging pathways compared to males.

Aging causes stress to every system in the body. Our ability to manage this stress declines with age, as energy-generating metabolic processes become less efficient. This in turn, makes us more susceptible to age-related declines in health. 

In female mice, the group discovered an ability to respond to stress by modifying their metabolism to make use of alternate means of producing energy. They noted that female mice, for example, could shift between different metabolic pathways for generating the energy needed to carry out vital cellular functions. 

According to their findings, GIT2 appears to coordinate this switching. 

The research team, led by Stuart Maudsley of the University of Antwerp analyzed the molecular networks that GIT2 participates in to investigate whether there is an order to a chaotic-looking system in his previous studies. All molecules inside a cell, such as proteins, metabolites, and various chemicals, work together in highly interconnected networks to make the cell function. You can picture these networks as a road map, where each destination is a cellular function, such as recycling old components, or generating energy. Only that the cellular roadmap is extremely complicated.

“Rough approximation, there are 1 million reactions every 10 seconds between 42 million proteins in one cell, that’s the complexity we’re dealing with”, said Maudsley in a presentation at the Eurosymposium on Healthy Aging in 2018. “Essentially, this is what we call a keystone analysis. We’re looking for proteins that actually could control the [hypothalamus] and control as many processes.” The team identified the protein GIT2 as one of the potential proteins.

Through partially reducing GIT2 protein expression in the hypothalamus of mice, the researchers analyzed the affected transcripts, which are RNA copies of genes and that serve as instructions for making proteins, to investigate the relevant molecular pathways. Found within the brain, the hypothalamus regulates multiple metabolic pathways by making and secreting hormones that carry information throughout our nervous system. By doing so, this organ acts as a master controller of the so-called “neurometabolic” communications network. They discovered that over half of the significantly altered transcripts were gender-unique, meaning that female and male mice respond to GIT2 distinctively. This yields insights into the gender-specific control of longevity.

Female mice downregulate pathways normally expected as part of the aging process, while their male counterparts upregulate those same processes. GIT2 acts as one of the coordinators of metabolic aging and stress sensitivity, especially in females. In response to GIT2, females prioritize metabolic diversity, expanding their range of metabolic strategies to obtain energy, and prepare the organism for the aging process. Males concentrate on maintaining neurosynaptic architecture, the structure of neurons and synapses in the brain.There has long been a known association between neurological health and longevity, but more studies are needed to fully understand the precise nature of this relationship.

“This functional bifurcation may have profound effects for aging trajectories in these mice and both genders in general,” wrote the authors of the study. “Hopefully, an enhanced understanding of these longevity-regulating networks will reveal crucial mechanisms by which healthspan may be therapeutically regulated.”  

Statistics show that females live longer in 176 out of the 178 countries, islands, and areas where the United Nations (UN) keeps records, according to the Demographic Yearbook published by the UN in 2014. The number predicts a difference in the aging of males and females. But over three-quarters of studies on aging and longevity exclusively used male models, according to the calculation of the Benayoun Lab at the University of Southern California. 

The current study not only provides insight into the fundamental differences in aging between females and males, it also allows us to develop more nuanced therapeutics, catered towards different genders.