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KLF4 Involved in Autophagy and Age-Related Vascular Dysfunction

There are any number of specific proteins associated with the progression of aging and its dysfunctions in one way or another. The overwhelming majority are not directly involved in the fundamental molecular damage that causes aging, but rather in the secondary consequences and reactions to that damage. It is therefore the case that they are poor targets for efforts to treat aging, because trying to manipulate the dysfunctional state of metabolism is a poor substitute for fixing the root cause damage that leads to that dysfunction. The research here is an example of the type, and the sort of investigations that result.

The maintenance of cellular and organismal homeostasis determines the progress of aging. On a cellular level, homeostasis is maintained, in part, through macroautophagy (hereafter referred to as autophagy), a conserved mechanism by which a cell achieves multiple goals, including clearance of misfolded proteins and organelle turnover with subsequent recycling of degraded constituents. As cells age, their ability to perform these functions declines. This likely leads to an unsustainable accumulation of protein aggregates, which ultimately present an obstacle to cellular survival. Indeed, studies of the distinct signaling networks in C. elegans that modulate lifespan have provided evidence of a central role for autophagy in many known longevity paradigms.

Thus loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes.

Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 (KLF4) functions to regulate autophagy in vascular endothelial cells and modulate blood vessel aging in mice. KLF4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging.

Link: https://doi.org/10.1038/s41467-017-00899-5

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