Many forms of mild stress produce a corresponding increase in cell maintenance activities that lasts for a while longer, improving cell function, improving tissue and organ function, and over time extending life by slowing the accumulation of some of the forms of damage that drive aging. Low nutrient availability, cold, heat, toxins, all of these can be beneficial at some level and duration of exposure. For example, the practice of calorie restriction produces an upregulation of the cell maintenance processes of autophagy, and this appears to be the crucial outcome that drives improved health and a slowed progression of aging.
It is unfortunate that these effects have a much smaller effect on aging in long-lived species versus short-lived species. It means that most of the interventions discovered to influence the pace of aging turn out to be a poor basis for human enhancement therapies to extend healthy life span. In the case of nutrient sensing and its ability to extend life past a season of famine, there are sound evolutionary reasons as to why short-lived species undergo a greater extension of life relative to their life span - a season is a long time for a mouse, not so long for a human. But it isn't all that clear as to why this should also apply to, say, the heat shock response, other than it potentially using many of the same underlying mechanisms as the calorie restriction response. In today's open access paper, researchers find that this assumption may not be correct, or at least that matters are more complex than this, leading by a winding and indirect path to the mitochondria.
HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling
Cells possess an array of protein quality control mechanisms collectively referred to as the proteostasis network (PN), which act to preserve proteome integrity. The PN coordinates protein synthesis, folding, disaggregation and degradation and integrates components of the translational machinery, molecular chaperones and co-chaperones and the proteolytic systems - the ubiquitin-proteasome system (UPS), and autophagy-lysosomal system - to ensure cell viability.
The cytosolic/nuclear arm of the PN is subject to regulation by heat shock transcription factor 1 (HSF-1), which protects the proteome by driving the expression of heat shock proteins (HSPs) that function as molecular chaperones. In line with its function, the knockdown of HSF-1 leads to increased protein aggregation, tissue dysfunction and decreased survival, whereas overexpression of HSF-1 maintains proteome integrity, promotes tissue health, and extends lifespan. While it is apparent that increasing HSF-1 activity is beneficial for longevity, our understanding of the mechanisms that act downstream of HSF-1 to prolong healthy tissue function remains limited.
It is widely believed that HSF-1 regulates ageing by upregulating the expression of HSPs. However, in addition to HSPs, HSF-1 also controls the expression of genes encoding cytoskeletal components, metabolic enzymes, ribosomal subunits, chromatin factors and components of the UPS. Moreover, recent work has demonstrated roles for autophagy, maintenance of the cytoskeleton and lipid regulation in HSF-1-mediated lifespan extension. These observations indicate that HSF-1 regulates longevity through mechanisms beyond HSP-mediated chaperoning of the proteome.
Here, we employ an RNA interference screen to identify the HSF-1 target genes that promote increased lifespan in C. elegans overexpressing HSF-1. We find that the sole worm ubiquilin, ubiquilin-1 (ubql-1), is necessary to increase lifespan. Ubiquilins are multifaceted, conserved shuttle proteins that localise to the cytoplasm and nucleus, where they function as chaperones that aid in the degradation of substrates through the ubiquitin-proteasome system and autophagy. Despite its central role in protein degradation, we find that ubiquilin-1 does not promote longevity by altering general proteostasis capacity. Instead it leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan.
Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.
View the full article at FightAging
