A shorter life may be the price an organism pays for coping with the natural assaults of daily living, according to researchers at NIEHS and their colleagues in Japan. Studying fruit flies, the scientists examined the relationship between lifespan and signaling proteins that defend the body against environmental stressors, such as bacterial infections and cold temperatures.

Because fruit flies and mammals share some of the same molecular pathways, the work may demonstrate how the environment affects longevity in humans.

Protein key to inflammation discovered

The new study from Shears and colleagues may provide a molecular basis for theory of aging. (Photo courtesy of Steve McCaw)

The study, published in the Proceedings of the National Academy of Sciences, identified a protein that moderates how fruit flies respond to inflammation. The protein is known as Methuselah-like receptor-10 (Mthl10).

The finding provides evidence for a theory of aging that suggests longevity depends on a delicate balance between proinflammatory proteins, which are thought to promote aging, and anti-inflammatory proteins, which are believed to prolong life. The inflammatory factors are influenced by what an organism experiences in its everyday environment.

Corresponding author Stephen Shears, Ph.D., who leads the NIEHS Inositol Signaling Group, explained that Mthl10 appears on the surface of insect cells and acts as the binding partner for a signaling molecule known as growth-blocking peptide (GBP). Once Mthl10 and GBP connect, they initiate the production of proinflammatory proteins. In turn, these proteins shorten the fruit fly’s life.

Inflammation vs. longevity

Removing the Mthl10 gene made the flies unable to produce Mthl10 protein and prevented GBP from binding to cells. As a result, the flies experienced low levels of inflammation and longer lifespans.

'Fruit flies without Mthl10 lived up to 25 percent longer,' Shears said. 'But they exhibited higher death rates when exposed to environmental stressors.'

Shears said the research suggests that the ability of a young organism to defend against repeated environmental stress may be an empty victory, because the animal may not live as long. He believes the research may contribute to the discovery of drugs that target excess inflammation induced by signaling proteins in humans, extending life.

The binding of GBP to Mthl10 promotes inflammation, which decreases the lifespan of a fruit fly. In contrast, the removal of GBP’s binding partner Mthl10, produces less inflammation and increases the lifespan of the fly. (Photo courtesy of NIEHS)

Exhaustive search for binding partner

NIEHS visiting fellow and first author Eui Jae Sung, D.V.M., Ph.D., said when he started the project in 2013, scientists did not know what cell-surface protein was working with GBP to promote inflammation.

So Sung, who works in the National Toxicology Program Cellular and Molecular Pathology Branch, began testing 1,700 compounds that could suppress production of every known cell-surface protein in the fruit fly. He looked for the protein that prevented GBP from binding and activating inflammation. He found several candidates, but all except Mthl10 were eliminated during further testing.

'After verifying that Mthl10 binds to GBP, our Japanese collaborators confirmed it through experiments in fruit flies,' Sung said.

Shears said their study proposes that the human counterpart to GBP is a protein called defensin BD2, but the nature of its binding partner is currently unknown. According to Shears, it is not always possible for humans to prevent illness and environmental stress from influencing the level of inflammation they experience.

'But there are other steps they can take,' Shears said. 'Another part of our fruit fly study shows that avoiding excess calorie intake, basically not over-indulging in too much carbohydrate and fat, may reduce levels of proinflammatory proteins.'

Citation: Sung EJ, Ryuda M, Matsumoto H, Uryu O, Ochiai M, Cook ME, Yi NY, Wang H, Putney JW, Bird GS, Shears SB, Hayakawa Y. 2017. Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress. Proc Natl Acad Sci U S A; doi:10.1073/pnas.1712453115 [Online 11 December 2017].