The TORC1 inhibitor Nprl2 protects age-related digestive function in Drosophila.

Junmeng Xi,Jiadong Cai,Youheng Wei,Ziheng Zhuang,Yue Hao,Yuanyuan Fu,Zhenbo Zhang,Wanhong Wei,Mary A Lilly,Yang Cheng

doi:10.18632/aging.102428

Abstract

Aging and age-related diseases occur in almost all organisms. Recently, it was discovered that the inhibition of target of rapamycin complex 1 (TORC1), a conserved complex that mediates nutrient status and cell metabolism, can extend an individual’s lifespan and inhibit age-related diseases in many model organisms. However, the mechanism whereby TORC1 affects aging remains elusive. Here, we use a loss-of-function mutation in nprl2, a component of GATOR1 that mediates amino acid levels and inhibits TORC1 activity, to investigate the effect of increased TORC1 activity on the occurrence of age-related digestive dysfunction in Drosophila. We found that the nprl2 mutation decreased Drosophila lifespan. Furthermore, the nprl2 mutant had a distended crop, with food accumulation at an early age. Interestingly, the inappropriate food distribution and digestion along with decreased crop contraction in nprl2 mutant can be rescued by decreasing TORC1 activity. In addition, nprl2-mutant flies exhibited age-related phenotypes in the midgut, including short gut length, a high rate of intestinal stem cell proliferation, and metabolic dysfunction, which could be rescued by inhibiting TORC1 activity. Our findings showed that the gastrointestinal tract aging process is accelerated in nprl2-mutant flies, owing to high TORC1 activity, which suggested that TORC1 promotes digestive tract senescence.

Highlights

Aging involves the progressive loss of physiological functions in all organs and tissues and increases vulnerability to death [1]
Mutation of nprl2 contributed to agerelated crop distension and digestive dysfunction, and this could be rescued by decreasing target of rapamycin complex 1 (TORC1) activity
Compared with the great progress had made on the midgut, little is known about the function of the Drosophila crop, which is analogous to the mammalian stomach

Summary

Introduction

Aging involves the progressive loss of physiological functions in all organs and tissues and increases vulnerability to death [1]. Age-related diseases, such as cancer, osteoporosis, and diabetes, are associated with an increase in cellular senescence [2, 3]. Many age-related diseases occur in young individuals in response to genetic and environmental insults [3]. TOR is an evolutionally conserved serine/threonine kinase that forms the catalytic subunit in two multi-protein complexes, TORC1 and TORC2, which have distinct structures and functions in metabolism [5]. TORC1 is sensitive to rapamycin and plays a central role in cell growth. It controls the balance between anabolism and catabolism in response to multiple inputs, including amino-acid availability, growth factor levels, and intracellular energy status. Cells can rapidly fine-tune their metabolic state in response to the environment by modulating the activity of TORC1 [8]

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