A new molecular pathway that controls lifespan and healthspan in worms has been identified by researchers at Case Western Reserve University School of Medicine. In a Nature Communications study published last week, it was shown that worms with excess levels of Kruppel-like transcription factors (KLFs) 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.
"We find that by artificially increasing or decreasing the levels of … Kruppel-like transcription factors, we can actually get …Caenorhabditis elegans to live for longer or shorter time periods," explains first author Nelson Hsieh, M.D./Ph.D. fellow at Case Western. "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."
"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," adds senior author Mukesh K. Jain, M.D., professor, vice-dean for medical sciences at Case Western.
Upon further investigation, the researchers discovered that KLF proteins work by controlling autophagy. Loss of this quality control mechanism is a hallmark of aging. As cells age, their ability to perform these functions declines. 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.