INSIGHT elife.elifesciences.org LONGEVITY Could a hormone point the way to life extension? Mice that have been genetically modified to produce high levels of fibroblast growth factor-21 live longer than mice with normal levels of this hormone. CYNTHIA KENYON stress or a shortage of energy, can extend life- Related research article Zhang Y, Xie Y, span in worms, flies and mice. Perhaps pharma- Berglund ED, Coate KC, He TT, Katafuchi T, ceutical techniques could be used to extend Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, human lifespans by modifying these or other Evans RM, Kliewer SA, Mangelsdorf DJ. life-extension pathways. 2012. The starvation hormone, fibroblast Now, writing in eLife, Yuan Zhang of the growth factor-21, extends lifespan in University of Texas Southwestern (UTSW) Medical mice. eLife 1:e00065. doi: 10.7554/eLife. Center and co-workers report that a hormone, 00065 called fibroblast growth factor-21 (FGF-21), can extend lifespan in mice (Zhang et al., 2012). When Image Lifespans of normal mice (blue line) food is withheld from an animal for 12 hours or and mice overexpressing FGF-21 (red) longer, liver cells produce this hormone, which then mobilizes fat stores in the liver, and promotes ill it be possible to slow the rate of the synthesis of glucose and ketones. FGF-21 also human aging and extend lifespan? reduces basal insulin levels and increases insulin WMaybe. Assuming that the first meta- sensitivity. In addition, it suppresses further growth zoans had short lifespans, gene changes have of the mice by preventing growth hormone from already extended our lifespans dramatically. triggering the production of IGF-1 (insulin-like Species with tissues much like ours can live far growth factor-1) in the liver. longer than we do, suggesting that perhaps we Previously, a collaboration between the UTSW could too. In some human families, living healthily group and researchers at New York University to age ninety or older is commonplace. With School of Medicine engineered mice with levels more knowledge of the genes responsible, it of circulating FGF-21 that were 5–10 times higher might be possible to design interventions to slow than normal (Inagaki et al., 2008). As a conse- down aging and increase healthy lifespan. quence, these animals switched on their star- In animals, many mutations can slow aging and vation response even though they continued to extend lifespan, in some cases dramatically. Most feed normally. Now Zhang et al. report that the Copyright Kenyon. This article is of these life-extending mutations affect biochem- median lifespans of these mice are increased—by distributed under the terms of the ical pathways that respond to nutrient, stress or 30% for male mice and 39% for female mice. Creative Commons Attribution energy levels. Inhibiting pathways that promote One consequence of high levels of FGF-21, dis- License, which permits unrestricted use and redistribution provided that the nutrient uptake or growth, or activating pathways ruption of the growth hormone/insulin/IGF-1 original author and source are credited. that normally help the organism respond to pathway, is already known to extend the lifespan Kenyon. eLife 2012;1:e00286. DOI: 10.7554/eLife.00286 1 of 3 Insight Longevity | Could a hormone point the way to life extension? of mice by ~50% (Coschigano et al., 2000). This differences between the outcomes of the two disruption is likely to be responsible for the studies might be partly due to other factors, such increase in the lifespans observed by Zhang et al. as genotypic differences between the groups. Other life extension pathways they examined (the Different strains of mice are now known to respond TOR, AMPK and sirtuin pathways) all appeared to caloric restriction in different ways: some strains normal in these mice. even live shorter, not longer. Because FGF-21 is a hormone, it should be While caloric restriction is not fully understood, possible to increase its level in humans. It is Zhang et al. show that it is unlikely to explain their possible that this will extend lifespan, because results because caloric restriction does not trigger there are already hints that inhibiting the growth FGF-21 production. Intriguingly, however, recurrent hormone/IGF-1 pathway promotes human lon- periods of starvation, administered in the form of gevity. First, genetic mutations that prevent cells intermittent, every-other-day feeding, can also from responding to IGF-1 are over-represented in extend lifespan in animals. This regime does centenarians (Suh et al., 2008), as are other not reduce overall caloric intake, as the animals rare DNA variants that reduce the activities of overeat when food is available, but it should trigger other components of this pathway, including the FGF-21 production. Moreover, in C. elegans, receptor for growth hormone (Y. Suh, personal where the mechanism has been examined, the communication). Second, DNA variants in the life extension produced by intermittent fasting FOXO3A gene have been linked to exceptional appears to act by inhibiting insulin/IGF-1 signal- longevity in at least eight studies across the ling and activating FOXO (Honjoh et al., 2009). world. FOXO proteins switch on genes that It would be interesting to know whether every- extend lifespan when insulin/IGF-1 signalling is other-day feeding might extend the lifespans of inhibited in animals, although we do not know primates. how these human DNA variants affect gene func- One of the most exciting features of many tion. Third, genome-wide association studies for long-lived worms, flies and mice is their resistance lon gevity highlight this pathway (Deelen et al., to age-related diseases such as cancer, athero- 2011). sclerosis and protein-aggregation disease. Since It was the ability of FGF-21 to help animals FGF-21 activates the same longevity pathways, it survive starvation that initially prompted Zhang is possible that this hormone might also confer and co-workers – who are based at UTSW, the resistance against disease. Unfortunately, like Howard Hughes Medical Institute and the Salk some other mice that are deficient in IGF-1, Institute – to test its role in aging. It has been these long-lived mice have low bone density, known for decades that a reduced calorie intake so we cannot recommend injecting FGF-21 (caloric restriction) can increase the lifespans of right now. rodents and other animals. When first discovered, during the Great Depression of the 1930s, caloric Cynthia Kenyon is at the University of California, restriction was assumed to work simply by reducing San Francisco, United States metabolic wear and tear. However, now we know [email protected] that it extends lifespan by engaging specific Competing interests: The author declares that no signalling pathways and changing patterns of competing interests exist gene expression. Published 15 October 2012 The results of a long-running caloric restriction experiment on primates were published recently References and, unexpectedly, it was found that the calori- Colman RJ, Anderson RM, Johnson SC, Kastman EK, cally restricted monkeys did not live any longer Kosmatka KJ, Beasley TM, et al. 2009. Caloric than control animals (Mattison et al., 2012). This restriction delays disease onset and mortality in rhesus finding was puzzling because caloric restriction had monkeys. Science 325:201–4. doi: 10.1126/science. seemed to extend lifespan in a previous study 1173635. Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ. (Colman et al., 2009). However, the monkeys in the 2000. Assessment of growth parameters and life span previous study had consumed a high-glycemic- of GHR/BP gene-disrupted mice. Endocrinology index diet, and the control animals (the only 141:2608–13. doi: 10.1210/en.141.7.2608. group in either study with a relatively short Deelen J, Uh HW, Monajemi R, van Heemst D, lifespan) were allowed to eat all they wanted. The Thijssen PE, Böhringer S, et al. 2011. Gene set analysis of GWAS data for human longevity highlights the take-home message here might be that a healthy, relevance of the insulin/IGF-1 signaling and telomere moderate diet will provide just as much benefit maintenance pathways. Age (Dordr). doi: 10.1007/ as more severe food limitation. However, the s11357-011-9340-3. Kenyon. eLife 2012;1:e00286. DOI: 10.7554/eLife.00286 2 of 3 Insight Longevity | Could a hormone point the way to life extension? Honjoh S, Yamamoto T, Uno M, Nishida E. 2009. from the NIA study. Nature 489:318–21. Signalling through RHEB-1 mediates intermittent doi: 10.1038/nature11432. fasting-induced longevity in C. elegans. 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