The demography of slow aging in male and female Drosophila mutant for the insulin‐receptor substrate homologue chico

Abstract

SummaryHypomorphic mutants affecting the Drosophila insulin/ IGF signal pathway are reported to increase longevity in females but not in males. To understand this sexdifference, we conducted a large-scale demographic study with three new isogenic strains of alleles at chico , the insulin-receptor substrate homologue. We verify that female dwarf homozygotes ( ch 1 / ch 1 ) and normal-sized heterozygotes ( ch 1 /+) are long-lived, as originally reported. We find for the first time that male heterozygotes are longlived relative to wildtype, by about 50%. The life span of male ch 1 / ch 1 is similar to that of wildtype but these dwarf males age at a slow demographic rate. The levels of demographic frailty and of age-independent mortality are elevated in ch 1 / ch 1 males, counteracting the effect of slow aging upon life expectancy. Mortality deceleration occurs amongst the oldest-old wildtype adults, as seen in many organisms. Remarkably, in similarly sized cohorts of male and female ch 1 / ch 1 and of male ch 1 /+ mortality deceleration is absent. Mortality deceleration is a phenotype of chico .

p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects

“…Further, long-lived chico mutants also have reduced Ref (2)P levels at the critical 3-4 week time point. 8,41 This suggests that basal autophagy rates are enhanced in neurons in which insulin ) are not significantly different from that of age-matched controls (canton-s, cs). Quantification of Ref (2)P levels are illustrated in Supplemental Figure 2A and B.…”

“…The initial low expression levels of Atg8a and ref (2)P may reflect the early developmental and metabolic defects that are caused by insulin signaling defects. 41,42 The further decline in expression is also reflected in Atg8a profiles found in 1-week-old and 4-week-old ref (2)P mutants, suggesting the decline in autophagy gene expression is a consistent feature of neuronal aging (Sup. Fig.…”

“…To explore this possibility we examined adult flies containing mutations in the chico gene (chico 1/2 , insulin receptor substrate homologue, IRS). 40,41 Highly conserved signaling pathways, defects in both the insulin and IGF (insulinlike growth factor) signals are known to enhance longevity and link caloric restriction with life-span extension. 42,43 The cellular mechanisms mediating these effects are not entirely clear, but both pathways are known to enhance TOR signaling (target of rapamycin), which in turn directly suppresses the activation of autophagy.…”

“…40,41 Ref (2)P and Actin densitometry readings were used to generate corrected values to illustrate protein levels of fly extracts prepared from different genotypes and ages (Fig. 4C).…”

Dissecting the genetics of longevity inDrosophila melanogaster

“…[1][2][3][4] This research, along with characterization of the types and rates of senescence and the importance of genes and gene classes in hypothesized mechanisms of aging regulation, is beyond the scope of this review. Instead, we describe the identification of specific aging genes in D. melanogaster that show general effects on organismal longevity, or lifespan, and discuss the complexity of the genetic architecture of lifespan as it affects genetics research and the evolution of longevity phenotypes.…”