Age-Related Increase in Lactate Dehydrogenase Activity in Skeletal Muscle Reduces Life Span in Drosophila

Metabolic adaptations occur with aging but the significance and causal roles of such changes are only partially known. In Drosophila, we find that skeletal muscle aging is paradoxically characterized by increased readouts of glycolysis (lactate, NADH/NAD+) but reduced expression of most glycolytic enzymes. This conundrum is explained by lactate dehydrogenase (LDH), an enzyme necessary for anaerobic glycolysis and whose expression increases with aging. Experimental Ldh overexpression in skeletal muscle of young flies increases glycolysis and shortens life span, suggesting that age-related increases in muscle LDH contribute to mortality. Similar results are also found with overexpression of other glycolytic enzymes (Pfrx/PFKFB, Pgi/GPI). Conversely, hypomorphic mutations in Ldh extend life span, whereas reduction in PFK, Pglym78/PGAM, Pgi/GPI, and Ald/ALDO levels shorten life span to various degrees, indicating that glycolysis needs to be tightly controlled for optimal aging. Altogether, these findings indicate a role for muscle LDH and glycolysis in aging.

Lack of Peroxisomal Catalase Causes a Progeric Phenotype inCaenorhabditis elegans

Studies using the nematodeCaenorhabditis elegansas a model system to investigate the aging process have implicated the insulin/insulin-like growth factor-I signaling pathway in the regulation of organismal longevity through its action on a subset of target genes. These targets can be classified into genes that shorten or extend life-span upon their induction. Genes that shorten life-span include a variety of stress response genes, among them genes encoding catalases; however, no evidence directly implicates catalases in the aging process of nematodes or other organisms. Using genetic mutants, we show that lack of peroxisomal catalase CTL-2 causes a progeric phenotype inC. elegans. Lack of peroxisomal catalase also affects the developmental program ofC. elegans, since Δctl-2mutants exhibit decreased egg laying capacity. In contrast, lack of cytosolic catalase CTL-1 has no effect on either nematode aging or egg laying capacity. The Δctl-2mutation also shortens the maximum life-span of the long lived Δclk-1mutant and accelerates the onset of its egg laying period. The more rapid aging of Δctl-2worms is apparently not due to increased carbonylation of the majorC. elegansproteins, although altered peroxisome morphology in the Δctl-2mutant suggests that changes in peroxisomal function, including increased production of reactive oxygen species, underlie the progeric phenotype of the Δctl-2mutant. Our findings support an important role for peroxisomal catalase in both the development and aging ofC. elegansand suggest the utility of the Δctl-2mutant as a convenient model for the study of aging and the human diseases acatalasemia and hypocatalasemia.

Regulation of gene expression is linked to life span in adult Drosophila.

Examination of gene expression and aging in adult Drosophila reveals that the expression of some genes is regulated by age-dependent mechanisms. Genetic mutations, Hyperkinetic and Shaker, which are known to shorten life span through an acceleration of the aging process, were used to study the expression of an enhancer trap marked gene. The temporal pattern of expression for such a marked gene shows scaling with respect to life span; it is altered in direct proportion to the life expectancy of the adult animal. This demonstrates that expression of this gene is controlled through mechanisms coupled to physiologic as opposed to chronologic age. Results provide direct evidence for linkage between the regulation of gene expression and life span and establish a model system for the genetic analysis of aging.