Interpreting interactions between treatments that slow aging

Abstract

SummaryA major challenge in current research into aging using model organisms is to establish whether different treatments resulting in slowed aging involve common or distinct mechanisms. Such treatments include gene mutation, dietary restriction (DR), and manipulation of reproduction, gonadal signals and temperature. The principal method used to determine whether these treatments act through common mechanisms is to compare the magnitude of the effect on aging of each treatment separately with that when two are applied simultaneously. In this discussion we identify five types of methodological shortcomings that have marred such studies. These are (1) submaximal lifespan-extension by individual treatments, e.g. as a result of the use of hypomorphic rather than null alleles; (2) effects of a single treatment on survival through more than one mechanism, e.g. pleiotropic effects of lifespan mutants; (3) the difficulty of interpreting the magnitude of increases in lifespan in double treatments, and failure to measure and model age-specific mortality rates; (4) the non-specific effects of life extension suppressors; and (5) the possible occurrence of artefactual mutant interactions. When considered in the light of these problems, the conclusions of a number of recent lifespan interaction studies appear questionable. We suggest six rules for avoiding the pitfalls that can beset interaction studies.

Mutation of C. elegans demethylase spr-5 extends transgenerational longevity

“…daf-16 knockdown also had no effect on spr-5(by101) egg laying (Supplementary information, Figure S4C). Because results obtained with RNAi are not as conclusive as null alleles [31] this experiment leaves open the possibility that the DAF-16 signaling pathway may be involved. To examine this signaling pathway more thoroughly, we also knocked down the intestinal ankyrin-repeat protein kri-1, which is required for DAF-16 nuclear localization and longevity in germline-deficient animals [32], in spr-5(by101) mutant worms.…”

Genome-Environment Interactions That Modulate Aging: Powerful Targets for Drug Discovery

“…One method is to identify genes that decrease or cancel out the life-extending effects of CR when mutated (Gems et al, 2002;Bishop and Guarente, 2007). More than 100 such genes have been identified in model organisms (D. Wuttke, C. Vora, J. P. de Magalhães, unpublished observations).…”

Protein Synthesis and Aging: eIF4E and the Soma vs. Germline Distinction

“…1 While the fidelity of mRNA translation does not appear to deteriorate during aging, numerous studies have established that general protein synthesis rates decline with age in a variety of organisms. [2][3][4][5][6][7] Both, biochemical data 7 and microarray expression profiling, 8 correlate lowered protein synthesis rates with senescent decline. Mitochondrial protein synthesis activity also diminishes markedly during aging.…”