Stress Resistance, Aging, and Late Life Diseases

Mutations that extend lifespan in invertebrates typically render the animals resistant to multiple forms of lethal injury, whether the threat comes from oxidative agents, heat, heavy metals, or irradiation. Indeed, this stress resistance seems likely to represent the mechanism by which these mutations delay the aging process. Thus presumably much of the cellular and extracellular pathology that produces dysfunction and increases mortality risk in older animals is held in abeyance by the same, poorly defined, defenses that permit nematodes and flies to survive when exposed to external stress in an experimental setting.

Genetic dissection of the relevant pathways has shown, surprisingly, that in normal, nonmutant worms, the levels of stress resistance, and thus resistance to aging, are actively diminished by specific DNA-binding transcription factors. These factors, whose human homologs are members of the FoxO family, are retained by evolutionary pressures because they provide reproductive advantages in the natural environment, in which animals must be able to quickly take advantage of transient access to nutrients. Genetic inactivation of these FoxO pathways in the laboratory produces mutant animals that are not ideally suited for natural conditions, but which are resistant to many kinds of stress and which age more slowly than normal. Studies of gene expression patterns in the long-lived mutant worms have shown that the FoxO proteins can trigger transcription of over 100 genes that together protect against many different forms of cellular damage. The list includes enzymes that destroy free radicals, heat shock proteins, and other chaperones that guard against misfolded proteins, recommended proteins that protect against infection, and chelating agents that bind toxic metal ions, among others.

The connection between induction of these stress-resistance pathways and late-life diseases has been shown by two sets of informative experiments. In the first, genetically identical worms were exposed to a brief, nonlethal heat stress, and physically separated into those that showed a strong response of chaperone proteins and those that did not. Worms with the most robust response to transient stress were found to be longer lived than those with lower stress responses. A second approach involved worms bearing genetic variants that cause aggregation of proteins and neurodegeneration (Huntington’s disease) in people; neurological dysfunction in these worms can be delayed, and in some cases prevented entirely, by augmentation of the FoxO-dependent stress-resistance pathways. Similarly, age-dependent increases in susceptibility to stress-induced cardiac arrhythmias in Drosophila can be significantly postponed by activation of FoxO-dependent protective pathways.

Studies of the relationship of stress resistance to aging in mammals are underway, but suggestive data have begun to emerge. Both CR diets and at least some of the long-lived endocrine mutant stocks show elevated levels of enzymes with antioxidant action, heavy metal chelators, and intracellular chaperone proteins, as well as have lower levels of oxidative damage to DNA, proteins, and lipids. Cells grown, in tissue culture, from long-lived Snell and Ames dwarf mutant mice, or from mice lacking GH receptor, are resistant to lethal injury caused by cadmium, peroxide, heat, a DNA alkylating agent (MMS), ultraviolet light, and paraquat (which induces mitochondrial damage by free radical generation). Mice prepared by CR or MR diets are resistant to liver damage induced by the oxidative hepatotoxin acetaminophen, and long-lived mutant mice are somewhat more resistant to death induced by paraquat injection. Stress resistance also seems to play a role in evolution of long-lived species in that cells from long-lived rodents and other mammals are resistant in culture to several forms of oxidative and nonoxidative damage. This work provides initial support for models that attribute variations in aging rate to differences in stress resistance pathways, but many questions remain unanswered at this early stage. It shows representative results for resistance to stress in long-lived mutant worms and cells from long-lived mutant mice, as well as data on resistance of CR and MR mice to an oxidative hepatotoxin.