Investigators have identified a new molecular pathway that controls lifespan and healthspan in worms and mammals. In a Nature Communications study researchers showed that worms with excess levels of certain proteins lived longer and healthier than normal worms. In addition, mice with excess levels of these proteins demonstrated a delay in blood vessel dysfunction associated with aging. The study has major implications for our understanding of aging and age-associated disorders.

"We find that by artificially increasing or decreasing the levels of a family of proteins called Kruppel-like transcription factors (KLF), we can actually get these small worms (Caenorhabditis elegans) to live for longer or shorter time periods," said first author. "Since this same family of proteins also exists in mammals, what is really exciting is that our data suggests the KLFs also have similar effects on aging in mammals, too."

Authors show the mammalian vascular factor Kruppel-like family of transcription factor 4 has a conserved role in augmenting autophagy and improving vessel function in aged mice. Kruppel-like family of transcription factor 4 expression also decreases with age in human vascular endothelium.

"The observation that KLF levels decrease with age and that sustained levels of KLFs can prevent the age-associated loss of blood vessel function is intriguing given that vascular dysfunction contributes significantly to diverse age-associated conditions such as hypertension, heart disease, and dementia" added senior author.

Upon further investigation, the researchers discovered that KLF proteins work by controlling autophagy--a recycling process cells use to clear debris, like misfolded proteins or normal molecular byproducts that build up in old age. Loss of this quality control mechanism is a hallmark of aging.

"As cells age, their ability to perform these functions declines," say the authors. "This likely leads to an unsustainable accumulation of toxic protein aggregates, which ultimately present an obstacle to cellular survival." Worms without KLF proteins cannot maintain autophagy and die early.

According to the researchers, the next step will be to study the precise mechanisms underlying how autophagy in cells lining blood vessels contributes to improved blood vessel function. They will also seek strategies to target KLF proteins in humans.

http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=722

https://www.nature.com/articles/s41467-017-00899-5