. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003 Jan 24;299(5606):572-4. PubMed.

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  1. Having been a neurologist in a former life, I have always wondered about how much aging plays a role in the neurodegenerative disorders. For some time it seemed that the debate (for it was a debate with little real information) fell into two categories. One point of view was that neurodegeneration is a disease and not a part of the normal aging process. The other viewpoint held that while it is a disease, it is age-related, so that the process of aging will impinge upon the timing and severity of the disorder. Some would go further to say that if people lived long enough, they would develop the neurodegenerative disorder, too. I think that these distinctions are less clear now. There certainly are a number of genetic and environmental factors that impinge upon the functioning and maintenance of the nervous system.

    With regards to the Blueher et al. article, I think it is reasonable to assume that the aging process does impact strongly on neurodegenerative diseases, and interventions that either delay or slow down the aging process, or lead to a more healthy state, will either reduce or ameliorate many of the neurodegenerative disorders.

    With regard to our work, the statement Bluher et al. make [about mitochondrial rate reduction extending life] we now know to be somewhat incorrect. Indy (for I’m not dead yet) long-lived flies have normal metabolic rates. At the time we published the Indy paper (Rogina et al., 2000), we did not know how a reduction in INDY led to life span extension. It was reasonable for Bluher et al. to think that the INDY protein is related to the mitochondria and would lead to a reduction in metabolism. However, we now know this not to be the case. The life-extending INDY protein is found on the plasma membrane, not the mitochondria (published last October, see Knauf et al, 2002), and in a paper in PNAS (see Marden et al., 2003), we show that the metabolic rate and physical activity of Indy long-lived flies is normal.

    Regarding the question of whether metabolism and ROS reduction mediate the beneficial effect of caloric restriction, for me the issue is how does caloric restriction really lead to life span extension? There are clearly many different effects seen in a calorically restricted animal. Which ones are relevant to life span extension and which are associated with the restricted calorie state, but do not contribute to the life span change? One way of looking at the Bluher et al. paper is that an effect on fat tissue may be a direct downstream part of the pathway from caloric restriction to life span extension. For me, since no one knows the pathway or mechanism by which caloric restriction causes life span extension, there is a lot of room for speculation.

    References:

    . Extended life-span conferred by cotransporter gene mutations in Drosophila. Science. 2000 Dec 15;290(5499):2137-40. PubMed.

    . Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14315-9. PubMed.

    . Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies. Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3369-73. PubMed.

    View all comments by Stephen Helfand
  2. The analyses of mice with adipose cell-specific knockout of the insulin receptor (FIRKO mice) by Bluher et al. provide at least three major advances in our understanding the mechanisms whereby insulin signaling and energy metabolism regulate life span. First, they show that the life span of mice with impaired adipose insulin signaling is increased without a decrease in calorie intake. This result seemingly shatters the hypothesis that caloric restriction extends life span simply by reducing mitochondrial metabolism and oxyradical production. Second, their findings suggest that insulin signaling in different cell types may have different effects on overall energy metabolism and life span. These findings are intriguing and support possibly related findings of Wolkow et al., 2000, who showed that insulin signaling in the nervous system regulates life span in C. elegans. It remains unclear how insulin signaling in adipose cells reduces life span, but this is certainly an important area for further investigation. One possibility is stimulation by insulin of the release of hormones, lipids or other molecules that have a pro-aging effect.

    Third, their data help to clarify an apparent contradiction between previous studies of insulin signaling and life span regulation in nematodes and rodents. Studies of C. elegans had shown that insulin signaling reduces life span, whereas increased insulin sensitivity (on a body-wide basis) is associated with increased life span in mammals. Caloric restriction, which extends life span, enhances insulin sensitivity in skeletal muscle while reducing fat mass. A generally similar increase in insulin sensitivity of nonadipose cells appears to occur in the FIRKO mice, although this needs to be examined in considerable detail. The initial phenotypes of FIRKO mice described in the study of Bluher et al. are remarkable, and suggest that these mice will provide a much-needed novel animal model for studies of mechanisms of aging and age-related disease.

    References:

    . Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science. 2000 Oct 6;290(5489):147-50. PubMed.

    View all comments by Mark Mattson
  3. Abandon your diets! Kahn and colleagues have examined the impact of selective loss of insulin receptors in adipose tissue on longevity in FIRKO (fat-specific insulin receptor knockout) mice. Disruption of insulin signaling appears not to be associated with diabetes or glucose intolerance. In addition, such mice have reduced fat mass, eat normally, and do not develop age-related obesity, which results in an overall extended mean life span.

    In the nematode and the fruit fly, decreased insulin-like signaling also appears to extend life span. Conversely, in mammals and humans, severe disruption of the insulin receptor leads to insulin resistance associated with diabetes and obesity, which extrapolates to a shortened life span. The FIRKO mouse exhibits loss of insulin signaling in fat tissue only. Together with normal food intake and reduced overall adiposity, the authors propose the FIRKO mouse as an in vivo model for mimicking caloric restriction. Although not investigated, the reduction in fat mass is likely due to an increased metabolic rate. However in rodents, caloric restriction appears to extend life span without altering metabolic rate. Well-established evidence supports beneficial effects of caloric restriction on aging and age-related diseases in several animal models, but the precise mechanisms of how or why this occurs remain unclear. It seems likely that leanness, rather than food restriction per se, may be the key element in increasing lifespan in FIRKO mice.

    Although preliminary, this study has broad implications. A 30 percent food-restricted diet is extremely unlikely to become a widespread practice among the general population without the aid of a caloric restriction mimetic agent. This study presents novel and exciting findings, which suggest that the anti-aging protective effects of caloric restriction might be achievable by indirect mechanisms, eliminating the need to diet.

    View all comments by TracyAnn Perry
  4. The paper from Kahn and coworkers is interesting and deserves greater attention. The expanded life expectancy due to leanness caused by a selective loss of insulin signalling in adipose tissue may point to an active metabolic role of that tissue. In this respect, work of other people suggests that leptin derived from adipose tissue may be involved in this process, see JF Caro et al., 1996; A Hamann et al., 1996; B Ahren et al., 1997; J Auwerx, B Staels, 1998; G Chen et al., 1996; N Barzilai et al., 1997. However, one important question remains unanswered: Is extended longevity accompanied by a stable quality of life, particularly with regard to mental health? It is tempting to asssume some relationship between Kahn's data and sporadic AD. In their textbooks published around 150 years and 100 years ago, Lorenz Geist, Emil Kraepelin, and Eugen Bleuler described the "classical" AD patient as being lean to gaunt in spite of normal to supernormal food intake. Provided that in sporadic AD, the observed disturbance in insulin signaling is not limited to neuronal tissue but also occurs in adipose tissue, a more general abnormality in insulin signaling in sporadic AD may be assumed. Studies on adipose tissue should clarify this issue.

    References:

    . Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes. 1996 Nov;45(11):1511-5. PubMed.

    . Regulation of circulating leptin in humans. Endocrine. 1997 Aug;7(1):1-8. PubMed.

    . Leptin. Lancet. 1998 Mar 7;351(9104):737-42. PubMed.

    . Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14795-9. PubMed.

    . Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Invest. 1997 Dec 15;100(12):3105-10. PubMed.

    . Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003 Jan 24;299(5606):572-4. PubMed.

    . Regulation of energy balance by leptin. Exp Clin Endocrinol Diabetes. 1996;104(4):293-300. PubMed.

    View all comments by Siegfried Hoyer