Longevity genomics across species

Abstract

Unbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms. Key pathways have been uncovered linking nutrient and growth factor cues to longevity. Quantitative measures of the degree to which aging is evolutionary conserved are now possible. A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.

Fig. (1)

Schematic of worm RNAi screens for increased life span. Individual ORFs can be specifically knocked down in C. elegans by feeding worms E. coli expressing double-stranded RNA corresponding to the ORF (RNAi). A library of ~15,000 different RNAi clones has been screened for long life span by identifying RNAi clones that have a high percentage of live animals on them after a length of time sufficient for most control (empty vector = EV) animals to have died. RNAi #2 in this example corresponds to a gene that limits life span.

Fig. (2)

An interative method for measuring yeast replicative life span for ~5000 single gene deletion strains. For each single gene deletion strain, replicative life span is determined initially for 5 mother cells. Each strain is classified as either “not long-lived” (NLL), “long-lived” (LL) or “ambiguous life span” (ALS), based on the 5-cell average. For strains classified as ALS, replicative life span is determined for additional mother cells, until a classification as either NLL or LL can be made. Verification of LL strains involves replicative life span analysis of an independently derived deletion mutant corresponding to the particular ORF.

Fig. (3)

A high-throughput method for measuring yeast chronological life span. Yeast deletion strains are aged in individual wells of 96-well microtiter plates. To assay viability, a small volume from the aging culture is inoculated into a larger volume of fresh media contained in a 96-well microtiter plate. The optical density of the new culture is measured after a fixed period of outgrowth under standard conditions. The relative optical density after outgrowth at different age-points is used to calculate the relative viability of each strain at each age-point. SL = short-lived. LL = long-lived.