KLF-mediated lifespan extension is dependent on autophagy. Klf-3 transcript levels in wild-type animals subjected to 2 days of chronic dietary restriction (sDR, OP50 diluted to 108 cfu/ml) (a) or inhibition of TOR signaling by RNAi against let-363 (b) starting from day 1 of adulthood. All lines were raised and maintained at 20 °C. *P-value < 0.05 by Student’s T-test, N = 3 biological replicates. c qPCR analysis of a panel of autophagy-related genes in day 1 klf-3 o/e and loss of function of both klf-3 and klf-1 animals compared to wild type. Double loss of function of klf-3 and klf-1 was performed as described previously utilizing the klf-3(ok175) mutant and simultaneous RNAi feeding targeting klf-1. All lines were raised and maintained at 20 °C. *P-value < 0.05 by Student’s T-test, N = 3 biological replicates (d, representative picture). e Autophagy in klf-3 o/e animals as determined by numbers of GFP::LGG-1 punctae in seam cells (red arrow denotes GFP-positive puncta) with knockdown of bec-1 in both wild-type and klf-3 o/e animals. *P-value < 0.05, # P-value ≤ 0.1 after one-way analysis of variance followed by the Tukey’s post hoc test. N = 10–20 animals counted. (f, wild-type representative image, g, klf-3 o/e representative image) Electron microscopy images of klf-3 o/e and wild-type animals in animals aged 9 days. Arrowheads indicate sizeable (≥500 nm) autolysosomes as recognized by single-membrane limited vacuolar structures with visible mixed cytoplasmic contents. Full images reproduced in Supplementary Fig. 11, with additional images. h Lifespan analysis of wild-type and klf-3 o/e animals fed RNAi bacteria targeting bec-1 from day 1 of adulthood. All lines were raised and maintained at 20 °C. P-value < 0.05 by Mantel–Cox log-rank tests. See also Supplementary Table 6 for details of lifespan analyses and replicate experiments. All error bars represent standard error of the mean (SEM)
Investigators at Case Western Reserve University School of Medicine and University Hospitals Health System have identified a new molecular pathway that controls lifespan and healthspan in worms and mammals. In a Nature Communications study published today, 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 Nelson Hsieh, MD/PhD fellow at Case Western Reserve University School of Medicine. “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” added Mukesh K. Jain, MD, Professor, Vice-Dean for Medical Sciences at Case Western Reserve University School of Medicine and Chief Scientific Officer, University Hospitals Health System.
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.
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. Said Hsieh, “As our population ages, we need to understand what happens to our heart and arteries, as we rely on them to function perfectly later and later on in our lives. Our findings illuminate what can happen during aging, and provide a foundation to designing interventions which slow these processes.”
http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=722
https://www.nature.com/articles/s41467-017-00899-5
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