Back-to-back papers in today’s Science shed new light on the role that insulin and heat shock proteins may play in the aging process. Gerald Shulman and colleagues at Yale University School of Medicine report that mitochondrial dysfunction may underlie insulin resistance in the elderly population. Cynthia Kenyon and colleagues at University of California, San Francisco, reveal that in roundworms, small heat shock proteins may not only be crucial for the extended lifespan offered by interrupting insulin signaling, but they may also prevent age-related aggregation of proteins with polyglutamine expansions. The latter finding may be of particular interest to those studying polyQ disorders such as Huntington's disease.
Insulin resistance is responsible for type 2 diabetes, which in developed countries is estimated to affect more than 30 million people over age 65. To understand the relationship between age and insulin, Shulman and colleagues subjected elderly (70 +/- 2 yrs) and young (27 +/- 2 yrs) volunteers to a battery of glucose tolerance and metabolic tests.
First author Kitt Falk Petersen and coworkers found that, during the glucose tolerance test, the elderly group had slightly, though not significantly, higher plasma glucose, and significantly higher plasma insulin (almost twofold) than did the young volunteers. Petersen traced the insulin resistance in the elderly to muscle cells, which had 45 percent higher triglyceride content than that found in muscles from young volunteers, suggesting some quantitative difference in metabolism.
Mitochondria are the power plants of muscle cells and are responsible for the metabolism of both lipids and carbohydrates. When Petersen et al. measured mitochondrial metabolism by whole-body magnetic resonance imaging, they found that mitochondria in the elderly were 40 percent slower at oxidizing intermediary metabolites and at generating ATP.
This study suggests that changes in mitochondrial oxidative metabolism are responsible for age-related insulin resistance, and, according to the authors, may also be important for aging in general. Previous work, however, has implicated fat tissue as the culprit in insulin resistance-mice bred to lack the fat cell-specific insulin receptor lived longer and were spared the insulin resistance that plagued their wild-type littermates (see ARF related news story).
In the second paper, Cynthia Kenyon and colleagues expand on earlier work from her own and other labs, which showed that mutating insulin receptors (DAF2 protein) extends lifespan in the roundworm Caenorhabditis elegans, as does overexpression of heat shock factor 1 (HSF1) and the transcription factor DAF16, which is normally turned off in response to insulin. In today's report, first author Ao-Lin Hsu connects these observations, asking if HSF1 and DAF16 work in concert.
Hsu and colleagues determined if the activities of the two factors are codependent. They found that DAF16 could induce protein expression (of superoxide dismutase and metallothionein) even in the absence of HSF1, while in the absence of DAF16, HSF could still activate heat shock proteins. This indicates that the two transcription factors do not directly act on each other, but does not exclude the possibility that they could activate a common pathway.
To answer this question, Hsu used DNA microarrays to search for heat shock proteins that may be regulated by insulin signaling. Sure enough, the authors found several small heat shock proteins (SHSPs) that are turned on in long-lived DAF2 mutants defective in insulin signaling. Significantly, HSF1 was absolutely required for this effect. Furthermore, Hsu found that in response to heat shock, activation of these HSPSs by HSF was dependent on DAF16.
Overall, these experiments indicate that the insulin and heat shock pathways, both of which have been linked to the aging process, impinge on some common targets, and that they act in opposition. For those studying neurodegeneration and cognitive decline, this may be particularly important because recent studies have shown that reduced glucose tolerance is associated with poor memory performance and atrophy of the hippocampus (see Convit et al 2003), and type 2 diabetes is epidemiologically linked to dementia. Hsu's last experiment is of particular interest. Using worms expressing a yellow fluorescent protein engineered to contain a 40-glutamine repeat, the authors show that the small heat shock proteins not only endowed the worms with greater longevity, but they also significantly reduced the aggregation of the polyglutamine reporter, thus explaining earlier observations that polyglutamine protein aggregation is delayed in long-lived worms (see Morley et al 2002).
"This is a very nice demonstration that heat shock factor and the heat shock response are working together with the insulin pathway, and it is consistent with a host of other data indicating that when you activate this pathway, worms go into a hunker-down mode where they upregulate their stress response," comments Chris Link, University of Colorado, Boulder. "But the model the authors propose requires careful analysis," he continued. "For example, there are three other genes, one of which is in the opposite orientation, between the potential DAF16 binding site and the start site of HSP16.1, so it is hard to imagine how DAF16 could directly activate expression of this heat shock protein."—Tom Fagan
- Convit A, Wolf OT, Tarshish C, de Leon MJ. Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2019-22. PubMed.
- Morley JF, Brignull HR, Weyers JJ, Morimoto RI. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10417-22. PubMed.
- Hsu AL, Murphy CT, Kenyon C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science. 2003 May 16;300(5622):1142-5. PubMed.
- Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003 May 16;300(5622):1140-2. PubMed.