A systematic genome-wide RNA interference screen was performed in the Caenorhabditis elegans lin-15b;eri-1 strain, which has an enhanced response to double-stranded RNA including the nervous system, to identify life-span regulatory factors. In total, 16,757 genes were examined, revealing 115 gene inactivations that extended life span. A more stringent longitudinal analysis revealed 18 gene inactivations that induced the greatest increase in life span (10-90%), all of which extended life span when inactivated either in eri-1 alone or in a second strain with an enhanced response to double-stranded RNA, eri-3. Most reduced the rate of aging, implying that animals aged more slowly. As was the case in previous studies, genes critical for metabolism caused the greatest extension of longevity. Extension of life span occurs through disparate mechanisms as increased resistance to thermal stress, oxidative damage, and decreased age pigment accumulation analysis of the 18 stronger positives failed to demonstrate a correlation between enhanced stress resistance and decreased lysosomal function. Consistently, aps-3 and lys-10, two genes annotated to have lysosomal functions, extended life span when inactivated without enhancing stress resistance. The results of this study reinforce the importance of metabolism, mitochondrial and lysosomal functions, genomic stability, and stress resistance on animal life-span determination.