This study found that reducing activity of the insulin/IGF-1 signaling pathway in the nematode C. elegans through genetic mutations or RNA interference can greatly extend lifespan without compromising health or activity levels. The longest-lived animals - those with reduced daf-2 activity through RNAi and germline removal - lived over six times longer than normal and remained highly active into old age, comparable to 500-year-old humans. This demonstrates that extreme longevity can be achieved without tradeoffs like lethargy, uncoupling longevity from quiescence.
This study found that reducing activity of the insulin/IGF-1 signaling pathway in the nematode C. elegans through genetic mutations or RNA interference can greatly extend lifespan without compromising health or activity levels. The longest-lived animals - those with reduced daf-2 activity through RNAi and germline removal - lived over six times longer than normal and remained highly active into old age, comparable to 500-year-old humans. This demonstrates that extreme longevity can be achieved without tradeoffs like lethargy, uncoupling longevity from quiescence.
This study found that reducing activity of the insulin/IGF-1 signaling pathway in the nematode C. elegans through genetic mutations or RNA interference can greatly extend lifespan without compromising health or activity levels. The longest-lived animals - those with reduced daf-2 activity through RNAi and germline removal - lived over six times longer than normal and remained highly active into old age, comparable to 500-year-old humans. This demonstrates that extreme longevity can be achieved without tradeoffs like lethargy, uncoupling longevity from quiescence.
Healthy Animals with Extreme still moving about on their plates without any prodding by the observer. Two of these ani-
Longevity mals are shown (Movie S1) at day 144. In
human terms, these animals would corre- spond to healthy, active 500 year olds. This Nuno Arantes-Oliveira,* Jennifer R. Berman, Cynthia Kenyon† indicates that extreme longevity can be un- coupled from quiescence. The life-spans of animals in nature range In the nematode Caenorhabditis elegans, thargic (4–8). This has suggested that extreme from a few weeks to more than a century. mutations that inhibit insulin/IGF-1 (insulin- longevity may require a metabolic tradeoff. Assuming that the ancestor of modern-day like growth factor 1) signaling, such as daf-2 Consistent with this, when daf-2(e1370) metazoans had a short life-span, changes in insulin/IGF-1 receptor mutations, can double mutants [which behave as class 2 mutants at genes during evolution have extended life-span the life-span of the animal (1). Removing the 25°C (3)] were subjected to gonad ablation more than 1000-fold. Though far short of this germ-line precursor cells also extends life- and daf-2 RNAi, they had very long life- achievement, these findings in C. elegans show span by approximately 60% (2). This life- spans (m ⫽ 100 days) but were lethargic and that remarkable life-span extensions can be pro- span extension is not a result of sterility; it dauer-like. However, when daf-2(e1368) an- duced with no apparent loss of health or vitality appears to be due to altered endocrine signal- imals [class 1 mutants (3)] were treated in the by perturbing a small number of genes and ing (1, 2). Removal of the germ line or the same way, not only did they have longer tissues in an animal. These life-span extensions, entire reproductive system of daf-2 mutants mean life-spans, they were quite active for which are the longest mean life-span extensions can further extend life-span: these animals most of their lives (9). For example at 120 ever produced in any organism, are particularly can live four times as long as normal (2). days, when approximately half of the animals intriguing because the insulin/IGF-1 pathway Strong reduction of daf-2 ac- controls longevity in many species, including tivity causes juvenile animals to mammals (1). enter a quiescent state of dia- pause called dauer. In contrast, References and Notes 1. M. Tatar, A. Bartke, A. Antebi, Science 299, 1346 (2003). partial loss-of-function daf-2 mu- 2. H. Hsin, C. Kenyon, Nature 399, 362 (1999). tants grow to adulthood and have 3. D. Gems et al., Genetics 150, 129 (1998). long life-spans. We found that 4. L. Partridge, D. Gems, Nature Rev. Genet. 3, 165 (2002). 5. P. L. Larsen, P. S. Albert, D. L. Riddle, Genetics 139, reducing daf-2 activity further by 1567 (1995). subjecting weak daf-2 mutants, 6. B. Lakowski, S. Hekimi, Science 272, 1010 (1996). such as daf-2(e1368), as young 7. C. Kenyon, data not shown. larvae to dal-2 RNA interference 8. S. Hekimi, D. Gems, P. Larsen, personal communication. 9. It was surprising that daf-2 (e1368, RNAi) animals (RNAi) produced larger increas- lived longer than class 2 mutants (3) without becom- es in life-span without triggering ing lethargic. Perhaps class 2 mutations do not simply dauer formation (Fig. 1). More- reduce gene activity, or perhaps daf-2 levels are quite low in class 2 mutants, and low activity early in life over, when we removed the re- (prior to the time at which we treated e1368 mu- productive systems of these tants with RNAi) produces dauer-like behavior in RNAi-treated animals, they lived adults. 10. Materials and Methods are available as supporting six times as long as normal. online material on Science Online. Fig. 1. Life-spans of experimental animals. N2 (wild type) on Whereas the mean life-span of control bacteria (black), m ⫽ 20.7 ⫾ 0.9 days, n ⫽ 56/49 11. N.A.O. was supported by a predoctoral fellowship wild type was 20 days, these an- [observed/uncensored events (10)]; daf-2(e1368) on control from the Portuguese Foundation for Science and Technology and by the Gulbenkian Foundation. J.R.B. imals had mean life-spans of 124 bacteria (blue), m ⫽ 32.4 ⫾ 1.2, n ⫽ 80/48, P ⬍ 0.0001; was supported by an HHMI Predoctoral Fellowship. days (Fig. 1). In fact, only 15% daf-2(e1368) on bacteria expressing daf-2 dsRNA (green), m ⫽ Supported by a grant from the NIH (ROI AG20932) of the animals died in the first 3 51.0 ⫾ 1.9, n ⫽ 80/68, P ⬍ 0.0001; gonad-ablated daf- to C.K. months. 2(e1368) on bacteria expressing daf-2 dsRNA (red), m ⫽ Supporting Online Material 124.1 ⫾ 5.9, n ⫽ 46/39, P ⬍ 0.0001. Like gonad-ablated www.sciencemag.org/cgi/content/full/302/5645/611/DC1 We were particularly inter- daf-2(e1368,RNAi) animals, N2, e1368, e1368(RNAi) and go- Materials and Methods ested in these animals’ “quality nad-ablated e1368 animals were healthy and active. We repeat- Movie S1 of life,” which can be addressed ed this experiment once, initiating RNAi at the L2 stage. Again, References by examining their level of activ- the gonad-ablated daf-2(e1368,RNAi) mutants were very 14 July 2003; accepted 5 September 2003 ity. Long-lived daf-2 mutants fall healthy and long-lived (m ⫽ 113 days). As observed previously into two classes. Class 1 mutants (2), gonad ablation did not further extend the life-span of daf-2(e1368) mutants. [In wild type and daf-2 mutants, abla- resemble normal animals, tion of the germ line extends life-span. In wild type but not whereas class 2 mutants are un- daf-2(e1370) animals, ablation of the somatic gonad as well Department of Biochemistry and Biophysics, Mission Bay Genentech Hall, 600 16th Street, Room S312D, coordinated and adopt a dauer- prevents this life-span extension. Thus, somatic gonad ablation University of California, San Francisco, San Francisco, like posture (3). Some class 2 may shorten life-span by increasing daf-2 activity. It seems CA 94143–2200, USA. mutations, either singly or in likely that e1370 and e1368 mutants differ in their response to *Present addresses: IN⫹ Center for Innovation, Tech- combination with other life-span somatic gonad ablation because of having different levels of nology and Policy Research Instituto Superior Téc- residual daf-2 activity (only e1368 mutants have sufficient nico, Technical University of Lisbon 1049-001, Lisboa, mutations, cause very long mean daf-2 activity to shorten life-span after somatic gonad abla- Portugal and ATGC Portugal Taguspark, Núcleo Cen- life-span extensions (up to 5.5- tion). This would explain why whole gonad (germ line plus tral 244 Porto Salvo, 2780-920 Oeiras, Portugal. fold); however, all of these somatic gonad) ablation can extend the life-span of daf- †To whom correspondence should be addressed. E- strains have been extremely le- 2(e1368,RNAi) but not daf-2(e1368) animals.] mail: ckenyon@biochem.ucsf.edu
www.sciencemag.org SCIENCE VOL 302 24 OCTOBER 2003 611
(Palgrave Studies in Religion, Politics, and Policy) Sabrina P. Ramet - Religion and Politics in Post-Socialist Central and Southeastern Europe - Challenges Since 1989-Palgrave Macmillan (2014)