Screening candidate longevity therapeutics using gene-expression arrays.
BACKGROUND
We review studies showing that CR acts rapidly, even in late adulthood, to extend health- and lifespan in mice. These rapid physiological effects are closely linked to patterns of gene expression in liver and heart. Non-human primate and human studies suggest that the signal transduction pathways responsible for the lifespan and health effects of caloric restriction (CR) may also be involved in human longevity. Thus, pharmaceuticals capable of mimicking the effects of CR (and other methods of lifespan extension) may have application to human health.


OBJECTIVE
We show that lifespan studies are an inefficient and theoretically problematic way of screening for longevity therapeutics. We review studies suggesting that rapid changes in patterns of gene expression can be used to identify pharmaceuticals capable of mimicking some positive effects of caloric restriction.


RESULTS
We present a traditional study of the effects of melatonin, melatonin and pregnenolone, aminoguanidine, aminoguanidine and alpha-lipoic acid, aminoguanidine, alpha-lipoic acid, pregnenolone, and coenzyme-Q(10) on the lifespan of mice. No treatment extended lifespan. However, because the mice die mostly of cancer, only chemopreventives active against specific cancers can be identified by such studies. The studies were also time-consuming and expensive. We discuss high-density microarray studies of the effectiveness of glucoregulatory drugs and putative cancer chemopreventatives at reproducing the hepatic gene-expression profiles of long-term and short-term CR. We describe the identification of one compound, metformin, which reproduces a subset of the gene-expression and physiological effects of CR.


CONCLUSIONS
Taken together, our results suggest that gene-expression biomarkers may be superior to lifespan studies for initial screening of candidate longevity therapeutics.
Spindler
Stephen R
SR
Department of Biochemistry, University of California, Riverside, Calif 92521, USA. spindler@ucr.edu
Mote
Patricia L
PL
D000375:Aging; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D031204:Caloric Restriction; D019587:Dietary Supplements; D020869:Gene Expression Profiling; D005820:Genetic Testing; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction
D015415:Biomarkers; D007328:Insulin; D007334:Insulin-Like Growth Factor I