Collectively, our findings indicate that daf-2, daf-16 and hsf-1 are required up to advanced age for protection against muscular Aβ proteotoxicity and that late life IIS attenuation can protect from further damage without extending lifespan (Fig. 5).
The parity in encoding performance between tph-1 and daf-7 expression and lifespan, along with the attenuation of lifespan response in the mutants, suggests that this neuronal representation has major functional information-carrying capacity.
However as several different physiological parameters are also coordinately altered during DR, such as insulin signaling [ 13] and cellular autophagy [ 14], it is therefore not possible to attribute exclusively this effect on lifespan to simply the attenuation of mtROS production.
That daf-7 and tph-1 act in food-responsive sensory neurons, together with the bidirectional attenuation of lifespan responses in the single and double mutants suggests that loss of tph-1 and daf-7 impairs the ability to sense and/or convey information about food levels, leading to a flattened response.
The present study shows that insulin pathway attenuation can also extend lifespan in males, presumably, through mechanisms not related to fecundity.
Moreover, inhibition of hyperfunction in downstream processes regulated by aging pathways, e.g. attenuation of protein synthesis, extends lifespan [ 98- 100].
Attenuation of insulin-like signaling extends lifespan in C. elegans.
We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation.
SIRT6 extends lifespan in male mice or prevents cardiac hypertrophy via the attenuation of IGF-AKT pathways (Kanfi et al., 2012; Sundaresan et al., 2012).
Further studies should reveal whether there are functional homologs of AF01 in higher eukaryotes and whether its tissue-specific and developmental stage-specific attenuation activates the mitochondrial misfolded protein response and lifespan extension.
