Worm study provides insight into aging

The Kruppel-like transcription factors (KLFs), a family of transcriptional factors, regulate autophagy and lifespan in the worm C. elegans, according to a study published online last week in the journal Nature Communications.

The study is carried out by Case Western Reserve University (CWRU) in collaboration with Kent State University, Lerner Research Institute, and Oberlin College.

Aging has long been a hot research field. With the global population aging, aging research will become more and more important. New findings in aging research would greatly improve the quality of life of people, including both young and old, and reduce health care costs.

The process of aging is linked with the maintenance of cellular and organismal homeostasis, and the maintenance of homeostasis is strongly associated with a natural, destructive mechanism, known as autophagy. The term autophagy means "self-eating". It is the segregation and degradation of damaged or unwanted cytoplasmic constituents. As cells age, the function of autophagy weakens, leading to accumulation of protein aggregates that eventually affects cell survival.

Autophagy is conserved across diverse species ranging from simple unicellular organisms like yeast to roundworms such as C. elegans to more complex systems, for instance mammals. A growing body of evidence suggests that autophagy is a pivotal regulator of longevity in many organisms, including C. elegans. CWRU researchers and others previously have found that in mammals, KLFs like KLF4 has a role in the regulation of autophagy. The zinc finger transcriptional factors KLFs are known to regulate proliferation, survival, metabolism, and response to stress. But whether and how KLFs affect the lifespan in C. elegans and mammals remain unclear.

In the present study, CWRU researchers demonstrated the requirement of KLFs for lifespan extension in C. elegans. In C. elegans, three KLF genes, KLF1, KLF2, and KLF3, have been associated with cellular metabolism and survival. To determine which KLFs may affect lifespan, the researchers performed loss-of-function analysis. They found that loss of single KLF genes had almost no effect on the lifespan of the worms, while double loss of KLF1 and KLF3 in any combination led to a significant reduction in the lifespan, in comparison with wide-type controls.

Next, CWRU researchers performed gain-of-function analysis, and discovered that worms overexpressing KLF3 displayed prolonged lifespan. Prior to this study, other scientists had shown that KLF1 overexpression also prolongs lifespan, but not significantly. In the further experiments, CWRU researchers uncovered that KLF3's effect on lifespan is dependent on its role in the regulation of autophagy.

Finally, the researchers conducted experiments in human cell lines and mice. The results proved that mammalian KLF4 regulates autophagy and KLF4 overexpression delays vessel aging through enhancing autophagy.

In conclusion, the study demonstrates a regulatory role of KLFs in autophagy and longevity in C. elegans. Similar mechanisms may be present in mammals. These findings have profound implications for aging research.
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