Sci. Aging Knowl. Environ., 25 June 2003
Vol. 2003, Issue 25, p. pe16
[DOI: 10.1126/sageke.2003.25.pe16]


Does Anti-Aging Equal Anti-Microbial?

Gordon J. Lithgow

The author is at the Buck Institute for Age Research, Novato, CA 94945, USA. E-mail: glithgow{at};2003/25/pe16

Key Words: anti-microbial • insulin • insulin-like growth factor 1 • bacteria • Caenorhabditis elegans

The process of aging has long been associated with susceptibility to infectious disease, with widespread changes occurring over time in the host response to microbes and parasites (1, 2). A prime motivation for basic research on aging is the belief that an understanding of the factors that cause aging will yield important information about the origins of age-related disease. No clearer example of this principle could be provided than the recent discovery that genetic mutations that confer extended life span on the nematode Caenorhabditis elegans also result in resistance to pathogenic bacterial infection (3). In this week's issue of Science, a report by Garsin and co-workers demonstrates that a signaling pathway that greatly influences the rate of aging also has spectacular effects on resistance to pathogenic bacteria (4) (see Garsin et al. Science Article).

C. elegans is an excellent system for the investigation of complex interactions between pathogens and hosts (4-6). One fruitful avenue of research is to search for genetic alterations, both in the host and in the pathogen, that influence interactions between host defenses and virulence factors produced by the pathogen. Such experiments can be performed in the nematode in a rapid, cost-effective fashion. For C. elegans, hundreds of genetic, environmental, and pharmacological interventions are available that alter the rate of aging (see SAGE KE Genes/Interventions Database). Therefore, this versatile organism is particularly well suited to the study of the effects of aging on host/pathogen interactions.

Garsin and co-workers (4) took advantage of these features to study the susceptibility of C. elegans to infection by Gram-positive and Gram-negative bacteria. They demonstrated that worms carrying mutations in the conserved insulin/insulin-like growth factor 1 (IGF-1) signaling pathway (see Johnson Review) are resistant to Enterococcus faecalis (Gram-positive), Staphylococcus aureus (Gram-positive), and Pseudomonas aeruginosa (Gram-negative) (Fig. 1). In particular, mutation of the daf-2 gene, which encodes an insulin/IGF-1-like receptor, leads to a fivefold enhancement of survival as compared to the wild type when the worms are challenged with Gram-positive pathogens. C. elegans is normally cultured in the presence of an auxotrophic mutant of Escherichia coli as a food source. The mutant daf-2 allele is known to confer a 100% increase in C. elegans life span (7), altering it from about 18 to 20 days to 35 to 40 days under these normal laboratory conditions. When E. coli is replaced with S. aureus, wild-type worms die in a couple of days, but the daf-2 mutant worms live about 10 days--a dramatic difference in survival. The age-1 gene encodes a phosphatidylinositol 3-kinase that functions in the insulin/IGF-1 pathway. Mutation of age-1 can lead to a 65% extension of life span and also has some beneficial antibacterial effects when worms are grown in the presence of S. aureus, although the single age-1 mutant allele tested did not yield the dramatic survival increase seen in daf-2 mutant worms.

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Fig. 1. The relation between aging and bacterial pathogens. The figure shows aspects of the insulin/IGF-1 pathway over a sea of adult C. elegans nematodes swimming on a lawn of E. coli bacteria. The insulin/IGF-1-like signaling pathway has a large influence both on aging rate and on the nematode's resistance to pathogenic bacteria. There may be some overlap in the mechanisms that promote resistance to both aging and disease, such as the action of antioxidant enzymes, which reduce intrinsic oxidative damage that may contribute to aging and counteract some of the pathogen's pro-oxidants, such as hydrogen peroxide. The insulin/IGF-1 signaling pathway may regulate a range of innate immunity functions. [Credit: Anders Olsen, Buck Institute]

In light of these results, it is of interest to discuss the normal cause of death in worms. A number of researchers are now tweezing apart the pathology that leads to aging and death in the worm. It appears that the standard laboratory food stock (the Gram-negative bacterium E. coli, strain OP50) can have detrimental effects (8-10). The life span of wild-type worms can be increased when they are grown on E. coli strain OP50 that has been treated with a bacteriostatic antibiotic that prevents bacterial growth (10). It appears that the final coup de grace is bacterial invasion. Consistent with this hypothesis, E. coli-derived RNA can be detected at high levels in old wild-type worms, but, interestingly, long-lived age-1 mutant worms have lower internal concentrations of bacterial RNA (11). This observation suggests that the long-lived mutants have lower levels of bacterial infection, which might contribute to the extended life span. Indeed, Garsin et al. have now shown this to be the case.

These results raise the possibility that the widespread reported longevity effects of the mutations in components of the insulin signaling pathways are due simply to an enhanced resistance to bacterial pathogens. However, when Garsin et al. fed worms Bacillus subtilis instead of E. coli, they observed an increase in the life span of both wild-type and daf-2 mutant worms. It appears that B. subtilis is a rather benign bacteria for C. elegans. In general, the degree of life span extension observed in bacterially infected daf-2 mutants is dependant on the pathogenicity of the bacteria to which the worms are exposed. In contrast, the effects of the mutations on longevity are always apparent, even when the worms are grown in the presence of dead bacteria (8) or in the absence of bacteria altogether (12). Taken together, these findings suggest that not all of the consequences of mutations that affect the insulin signaling pathway can be ascribed to the combating of bacterial pathogenicity and that the major effects on aging are due to intrinsic factors.

How do worms fight bacterial infection? A few factors associated with innate immunity have been described (13) in this organism. For example, the Gram-negative bacteria Serratia marcescens induce C. elegans to produce lectins and the bacteriolytic enzyme lysozyme. In other animals, lectins have a number of roles in innate immunity, including aiding in the recognition of surface glycans on pathogens and thus stimulating phagocytosis. Increased expression of lysozyme, on the other hand, can lead to resistance to bacterial infection, presumably because this enzyme digests the bacterial peptidoglycan cell wall (14). Many of the worm genes induced by bacterial infection are under the control of DBL-1 (decapentaplegic bone morphogenetic protein-like 1), which functions in the tumor necrosis factor beta (TGF-{beta}) pathway (14), which is critical for normal development. C. elegans also produces the antibacterial factor ASABF, a peptide that exhibits potent Gram-positive bactericidal activity (15, 16). It will be of interest to learn whether the production of any of these factors is elevated in daf-2 or age-1 mutants.

The discovery of an association between longevity and resistance to microbial attack is consistent with a general trend in aging-related research: that longevity and stress tolerance are often coupled. The worm provides much evidence for a direct mechanistic link between environmental stress resistance and life span determination (17). For example, overexpression of a heat shock protein gene that is up-regulated in long-lived age-1 mutants (18) is sufficient to confer stress resistance and longevity (19) (see "Good Housekeeping"). Reduced insulin/IGF-1 signaling confers resistance to heat shock, heavy metals, oxidative stress, and ultraviolet radiation (20-24). There may be an overlap between an organism's ability to maintain homeostasis in the face of stress and the degree of its response to pathogens (25). For example, compared to wild-type worms, age-1 mutants exhibit elevated levels of resistance to oxidative stress and maintain higher concentrations of antioxidant enzyme activities with age (20, 21, 24, 26, 27). The protective role of antioxidant mechanisms in fighting bacterial infection in C. elegans has been previously demonstrated. When worms are exposed to the Gram-positive bacterium Streptococcus pyogenes, they die rapidly, not of infection, but apparently from the lethal action of hydrogen peroxide produced by the pathogen (28), and death can be prevented by the administration of catalase to the growth medium. Because both daf-2 and age-1 mutants exhibit elevated catalase enzyme activity (20), this mechanism may provide both resistance to some bacteria and strengthen the defenses against endogenously produced reactive oxygen species, thus slowing the aging process (see "The Two Faces of Oxygen").

The fact that the IGF-1 signaling pathway appears to influence the life span of laboratory rodents (29) (see "One for All") as well will no doubt get researchers thinking about the implications of this work for mammalian infectious disease and aging. How might these findings in the worm augment our understanding of human aging? In many ways, the human life-style resembles that of laboratory animals in that many of the extrinsic hazards of life are minimized. But whilst humans are generally not the subjects of predator attention, they are still exposed to a wide and perhaps increasing range of pathogenic microbes. The availability of antimicrobials, including antibiotics, may sustain life, but the immunological consequences of exposure, such as the release of cytokines and chemokines and the inflammatory response, are inescapable. In contrast, great care is taken to ensure that colonies of aging rodents experience minimal exposure to microbes (see "Spoiled Stores"). In this regard, the laboratory mouse bathed in pathogen-free air may not always constitute the best representation of the human experience.

Because of the findings of Garsin et al., many new questions have arisen regarding the worm and its bacterial invaders. Neither the specific innate immunity functions at play in the daf-2 mutants nor the precise mode of death are known. Clearly, for some bacterial species, virulence factors will be important; but for others, indirect damage from the worm's own innate response may be the major determinant of survival. When worms die, is it the result of a last-ditch attempt to prevent systemic infection? The worm may provide some valuable lessons at the interface of aging and infection.

June 25, 2003
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Citation: G. J. Lithgow, Does Anti-Aging Equal Anti-Microbial? Sci. SAGE KE 2003, pe16 (25 June 2003);2003/25/pe16

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