Sci. Aging Knowl. Environ., 11 February 2004
Vol. 2004, Issue 6, p. pe6
[DOI: 10.1126/sageke.2004.6.pe6]


Search for Methuselah Genes Heats Up

Valter D. Longo

The author is in the Leonard Davis School of Gerontology, Division of Biogerontology, University of Southern California, Los Angeles, CA 90089-0191, USA. E-mail: vlongo{at}

Key Words: stress • heat shock • transcription

Over the past 10 years, molecular geneticists have identified signal transduction pathways that regulate longevity in yeast, worms, flies, and mice. The inactivation of these pathways causes changes in gene expression that are normally associated with entry into periods of starvation. Among the genes that are consistently up-regulated in long-lived mutants are those that encode stress resistance proteins, specifically proteins that protect against oxidative and thermal damage. Until recently, expression of pro-longevity stress resistance genes in the worm Caenorhabditis elegans was believed to be mostly under the control of the DAF-16 transcription factor (see Johnson Review). In a recent article in Molecular Biology of the Cell, Morley and Morimoto (1) show that stress resistance genes that extend longevity are also regulated by the transcriptional activator heat shock factor 1 (HSF-1) independently of DAF-16, confirming recent studies by the Kenyon laboratory (2) (see "Vital Collaboration").

Work in yeast and worms has shown that transcription factors that regulate multiple stress resistance genes mediate the life span extension observed in mutants with reduced glucose or insulin-like growth factor (IGF-1) signaling (the daf-2 pathway in worms), respectively. Yeast transcription factors Msn2p and Msn4p, which are required for longevity extension in mutants with reduced activity of the Ras2p/ Cyr1p/protein kinase A pathway (see Kaeberlein Perspective and "Live Long and Ferment"), regulate the expression of many stress resistance proteins, including the heat shock protein 70 (Hsp70) family of chaperones (3, 4). Another protein that regulates transcription of Hsp70 and other heat shock proteins in yeast is Rim15p, a serine/threonine protein kinase that induces sporulation and is required for longevity extension in yeast that lack the protein kinase Sch9p; Sch9p is involved in a nutrient signaling pathway and is a functional homolog of mammalian Akt, which is part of the insulin/IGF-1 signaling pathway (see Bartke Viewpoint and "One For All") (5, 6).

In C. elegans, the role of heat shock proteins in the aging process was initially suggested by the observation that sublethal heat shock extends the worm life span (7). More recently, overexpression of either HSF-1, a transcription factor that regulates response to heat and oxidative stress, or Hsp70, a heat-induced chaperone protein, was shown to extend longevity, whereas inhibition of HSF-1 expression with RNA interference (RNAi) shortened the life span of both wild-type and long-lived daf-2 worm mutants (2, 8-10). Overexpression of Hsp70 also increases longevity in flies (11). The effect of HSF-1 on aging in nematodes appears to be mediated by several heat shock proteins, including HSP-16.1, HSP-16.49, HSP-12.6, and SIP-1. These proteins may slow down aging in part by acting as molecular chaperones that prevent or delay the aggregation of unfolded or damaged proteins (2).

The study by Morley and Morimoto, which confirms previous results by Hsu et al. (2) and Garigan et al. (8), also investigates the role of tissue-specific expression of HSF-1 on life span regulation. They found that overexpression of HSF-1 in neurons or body-wall muscle cells has the largest effect on longevity (15% extension), whereas intestinal overexpression extends life span by 7%. The role of heat shock proteins in regulating aging in multiple tissues was confirmed by their finding that inhibition of HSF-1 activity in either neurons or muscle cells reduces life span extension in age-1 (hx546) mutants; age-1 encodes a phosphoinositol 3-kinase that is part of the daf-2 signaling pathway. However, the life span of age-1 mutants was not decreased significantly by inhibition of HSF-1 in the intestine. By contrast, Libina et al. found that restoring DAF-16 activity exclusively in the intestine increases longevity in daf16(-) worms with mutations in the daf-2/age-1 pathway (12) (see "Visceral Reaction"). In this study, the authors also found that overexpression of DAF-16 in one tissue can up-regulate DAF-16 activity in other tissues. They propose that DAF-16 in signaling cells (neurons and intestine) may regulate the release of hormones and peptides that stimulate daf-16 expression in target tissues. They also propose that DAF-16 in the intestine can regulate longevity independently of DAF-16 in target tissues. Thus, HSF-1 may be one of the mediators of a cell-nonautonomous DAF-16-dependent effect on longevity (Fig. 1).

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Fig. 1. A model for the regulation of longevity and stress resistance by transcription factors DAF-16 and HSF-1 in C. elegans.

In addition to the heat shock proteins previously shown to extend longevity by Hsu et al. (2), Morley and Morimoto (1) also identified novel life-span related proteins. They show that inhibition with RNAi of several heat shock protein genes whose transcription is regulated by HSF-1, including hsp-16 and sip-1, but also C30C11.4, C12C8.1, and daf-21, results in a reproducible 8 to 13% reduction in the life span of age-1 mutants. Finally, they show that daf-16 and hsf-1 are required for dauer formation induced by age-1 mutations at 27°C, suggesting that both transcription factors extend longevity by up-regulating proteins that are normally required to overcome long starvation periods.

Increased expression of the HSF1 gene is also associated with extended chronological life span in yeast. Double deletion of the yeast hsc82 and cpr7 genes, which encode components of the Hsp90 chaperone complex, increases HSF1 gene expression and stress tolerance and extends the yeast chronological life span, although it does not increase the budding potential of individual mother cells (replicative life span) (13). Analogous to worm HSF-1 and DAF-16, yeast transcription factors Hsf1p and Msn2p/Msn4p can control different sets of stress resistance proteins but also play overlapping roles in regulating Hsp26, Hsp30, and Hsp104 (4). Considering the many similarities between the pathways that regulate chronological aging in yeast and worms, it will be interesting to test whether yeast Hsf1p is required for life span extension in ras2{Delta} and sch9{Delta} mutants and whether it may function independently of longevity-enhancing transcription factors Msn2p/Msn4p and protein kinase Rim15p. A role for Hsf1p in regulation of the chronological life span of unicellular Saccharomyces cerevisiae that is analogous to the function of HSF-1 in worms would strengthen the hypothesis that the regulation of longevity is conserved (14) and may suggest that HSPs can slow aging in a cell-autonomous manner, as shown for another stress-activated protein, manganese superoxide dismutase (MnSOD) (15).

Mitochondrial MnSOD, whose expression is activated by oxidative stress, has been implicated in the mediation of longevity extension in both long-lived yeast ras2 and sch9 mutants and in long-lived C. elegans with reduced insulin-like signaling (15, 16). Unless mitochondrial superoxide or MnSOD turns out to affect longevity by regulating other proteins and pathways, we can assume that increased protection against superoxide-mediated damage can extend longevity in yeast and worms. In fact, overexpression of SODs increases the life span of both yeast and flies (15, 17, 18). By contrast, as Morley and Morimoto point out, molecular chaperones can affect the expression and function of many proteins. For example, Hsp70 can inhibit mammalian apoptosis by binding to Apaf-1 and blocking apoptosome assembly (19). Hsp70 can also arrest DNA synthesis and mitogenesis by binding to Bag-1 (a co-chaperone for Hsp70) and displacing the Raf-1 kinase (20). Thus, heat shock proteins may slow down aging by preventing the accumulation of damaged proteins (a cell-autonomous function), but may also affect longevity by acting on downstream targets (cell-nonautonomous functions) that have not yet been identified.

The new studies by Morley and Morimoto and by Libina et al. provide important data on the effect of tissue-specific expression of the daf-16 and hsf-1 genes on aging (Fig. 1). The disentangling of the complex thread of activities responsible for the regulation of starvation response phases and longevity is beginning to reveal that the expression of many genes must be altered to extend the life span. The list of pro-longevity genes includes those that encode proteins that protect against oxidative and thermal stress, but is also likely to include genes associated with repair and replacement of damaged molecules and proteins. The combination of studies aimed at separating the cell-autonomous from cell-nonautonomous effects of longevity-enhancing proteins in multicellular organisms, with further studies in unicellular S. cerevisiae, other animal systems, and mammalian cell cultures, should soon illuminate the molecular and cellular networks responsible for the regulation of life span in eukaryotes.

February 11, 2004
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Citation: V. D. Longo, Search for Methuselah Genes Heats Up. Sci. Aging Knowl. Environ. 2004 (6), pe6 (2004).

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