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. 2004 Feb;15(2):657-64.
doi: 10.1091/mbc.e03-07-0532. Epub 2003 Dec 10.

Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones

James F Morley  1 , Richard I Morimoto
Affiliations

Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones

James F Morley et al. Mol Biol Cell. 2004 Feb.

Abstract

The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the regulation of life span. We therefore examined the role of heat shock factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual molecular chaperones, transcriptional _targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. The interaction of ILS with HSF-1 could represent an important molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress.

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Figures

Figure 1.
Figure 1.
Suppression of longevity associated with insulin-like signaling mutants by hsf-1(RNAi). (A) Life span measurements of wild-type (N2) and age-1(hx546) mutant animals grown on bacteria transformed with RNAi vectors for daf-16, hsf-1, or empty vector as indicated. (B) Life spans of daf-2(e1370) and old-1(zIs3000) animals with or without hsf-1 RNAi. (C) Comparison of shortened life span observed in daf-16(mgDf50) null mutants grown on control or hsf-1 RNAi bacteria. For statistical analysis (see Table 1). (D) Dauer formation of wild-type (N2) or age-1(hx546) animals grown at 27°C on the indicated RNAi bacteria. Data are mean ± SEM of duplicate plates from one experiment. Three independent trials gave similar results. (E) Epifluorescence images demonstrating expression of a C12C8.1(hsp70)::gfp reporter gene in wild-type(N2) or hsf-1(RNAi) animals after a 1-h heat shock at 33°C followed by 8 h of recovery.
Figure 2.
Figure 2.
HSF-1 acts in multiple tissues to regulate life span. (A) Life span of wild-type (N2) or transgenic animals expressing marker gene (myo-2::gfp) alone or in combination with let-858::hsf-1 or let-858::hsf-1Δ (encoding residues 290-671 of C. elegans HSF-1). (B) Life spans of transgenic animals expressing marker alone (myo-2::gfp) or in combination with hsf-1 in body-wall muscle (unc-54::hsf-1), intestine (vha-6::hsf-1), or nervous system (F25B5.3::hsf-1). Data are representative of experiments with two independent transgenic lines. No significant differences were noted between the duplicate lines. The data reported represent two independent trials that yielded similar results. In each case, the appropriate control was tested in parallel in the same experiment. For statistical analysis, see Table 2.
Figure 3.
Figure 3.
HSF-1 is required in multiple tissues for longevity of age-1(hx546) animals. (A) Life spans of age-1(hx546) expressing marker alone (myo-2::gfp) or in combination with hsf-1 dominant negative (HSF-1 DN) in body-wall muscle, intestine, or nervous system of age-1(hx546) animals. Data shown are representative of results from two independent transgenic lines expressing each construct. No significant differences were noted between the duplicate lines. Experiments were performed in two independent trials with similar results. For statistical analysis, see Table 2. (B) Epifluorescence images illustrating expression of a C. elegans hsp-70::gfp reporter after heat shock in wild-type or transgenic animals expressing HSF-1 dominant negative in body-wall muscle cells. Arrowheads, body-wall muscle cells. Arrows, pharynx.
Figure 4.
Figure 4.
Molecular chaperones are required for age-1(hx546) longevity. (A-H) Longevity curves for age-1(hx546) animals grown from young adulthood on bacteria expressing control vector or the indicated RNAi bacteria. All life spans were measured concurrently and vector control data shown is the same in each panel. The data reported represent two independent trials that yielded similar results. In each case, the appropriate control was tested in parallel in the same experiment. For statistical analysis, see Table 4. (I-K) Analysis of RNAi inactivation of Hsp40 (I, 3 = T05C3.5, 4 = F39B10.2) and Hsp70 (J, 5 = hsp-1, 6 = C30C11.4, 7 = C12C8.1) and Hsp90 (daf-21) genes by using RT-PCR. Total RNA was extracted from 3-d-old animals using TRIzol reagent after a 1-h heat shock at 33°C. Amplification of actin (A) was used as a control. Consistent with the high degree of sequence identity between Hsp70 family members, some cross-interference with expression of C12C8.1 expression is observed in C30C11.4 RNAi.
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