A conserved regulatory system for aging.

The similarities between these regulatory systems in worms, flies, and yeast are striking. First, each serves a similar biological function, allowing animals to postpone reproduction during unfavorable environmental conditions (Figure 1(Figure 1). Second, each regulates a similar set of processes: oxidative stress resistance, food utilization pathways, reproduction, and lifespan. Third, the systems are composed, at least in part, of homologous genes and pathways (Figure 2(Figure 2).Together these similarities suggest that this regulatory system arose early in evolution (see Kenyon 1996xKenyon, C. Cell. 1996; 84: 501–504Abstract | Full Text | Full Text PDF | PubMed | Scopus (45)See all References, Tissenbaum and Guarente 2001xTissenbaum, H.A and Guarente, L. Nature. 2001; 410: 227–230Crossref | PubMed | Scopus (1205)See all References). Its selective value should be enormous. When food becomes limiting, an animal lacking this system would either die of starvation, or produce progeny that die of starvation. In contrast, with this food-sensing system in place, as food declines, the animal begins to build up fat and/or glycogen reserves, elaborates stress-resistance mechanisms, and delays or suspends reproduction until food is restored. It also activates pathways that extend lifespan, which increases the organism's chance of being alive and still youthful enough to reproduce if it takes a long time for conditions to improve. Each of the diapause-linked processes, such as production of food storage reserves, or the suspension of reproduction, would have selective value on its own. Enhanced stress resistance could protect the animal from heat or toxins that cause oxidative damage (Mahajan-Miklos et al., 1999xMahajan-Miklos, S, Tan, M, Rahme, L.G, and Ausubel, F.M. Cell. 1999; 96: 47–57Abstract | Full Text | Full Text PDF | PubMed | Scopus (424)See all References(Mahajan-Miklos et al., 1999). Because each has intrinsic value, there is no reason a priori for any one of these traits to cause lifespan extension. Thus, the fact that so many of these traits can be uncoupled from lifespan extension genetically in model organisms need not be surprising.It is possible that this conserved system also operates in mammals (see Guarente and Kenyon 2000xGuarente, L and Kenyon, C. Nature. 2000; 408: 255–262Crossref | PubMed | Scopus (869)See all References, Clancy et al. 2001xClancy, D, Gems, D, Harshman, L.G, Oldham, S, Stocker, H, Hafen, E, Leevers, S.J, and Partridge, L. Science. 2001; 292: 104–106Crossref | PubMed | Scopus (824)See all References, Tatar et al. 2001xTatar, M, Kopelman, A, Epstein, D, Tu, M, Yin, C, and Garofalo, R.S. Science. 2001; 292: 107–110Crossref | PubMed | Scopus (884)See all References). Mutant mice that lack the pituitary gland develop into long-lived dwarfs (Bartke, 2000xSee all References(Bartke, 2000). These mice have reduced levels of several hormones, including IGF-1 (Brown-Borg et al., 1996xBrown-Borg, H.M, Borg, K.E, Meliska, C.J, and Bartke, A. Nature. 1996; 384: 33–34Crossref | PubMedSee all References(Brown-Borg et al., 1996), which is produced in response to pituitary growth hormone. Interestingly, small dogs, which have low levels of IGF-1, live longer than large dogs. The finding that, in flies, the insulin/IGF-1 system regulates size and lifespan independently of one another suggests that these mutant mice and small dogs might be long-lived even if they were not small. Caloric restriction, too, may extend lifespan by impacting an insulin/IGF-1 pathway, since it reduces the level of circulating insulin and IGF-1. Rodents that are calorically restricted during development are small, but rodents that are calorically restricted during adulthood are normal in size but still live long. Thus, again, size and longevity can be uncoupled.Insulin/IGF-1 pathways have increased greatly in complexity during evolution. Worms and flies have only one insulin/IGF-1 receptor, whereas vertebrates have at least three. Thus, it is possible that a lifespan regulatory function might be distributed among different branches of this endocrine system. In this regard, it is interesting that loss of the insulin receptor in the neuroepidermis decreases mouse fertility (Bruning et al., 2000xBruning, J.C, Gautam, D, Burks, D.J, Gillette, J, Schubert, M, Orban, P.C, Klein, R, Krone, W, Muller-Wieland, D, and Kahn, C.R. Science. 2000; 289: 122–2125Crossref | Scopus (1240)See all References(Bruning et al., 2000). The same is true of worms (Apfeld and Kenyon, 1998xApfeld, J and Kenyon, C. Cell. 1998; 95: 199–210Abstract | Full Text | Full Text PDF | PubMed | Scopus (211)See all References(Apfeld and Kenyon, 1998), and possibly flies as well. It would be interesting to learn whether these mice, like the worms and flies, are long lived.Aging proceeds at different rates in different animals. A mouse lives roughly two years; a bat, about 30–50; and a parrot, 90. How did these differences evolve? There must have been many mutations that increased lifespan during evolution, since all animals evolved from a common precursor that probably did not live very long. Longer lifespans may have evolved through changes in genes that regulate the rate of aging. For example, changes in insulin/IGF-1 pathway components could play a role in the evolution of lifespan, and this is suggested by the longevity of small dogs. This model is attractive because there is evidence that much of evolution occurs by changes in regulatory genes. In general, evolutionary biologists have not embraced the idea that aging is regulated, because there can be no selection for longevity once reproduction is complete and the progeny are able to live independently. However, the benefit of combining lifespan extension with other traits during diapause (particularly delayed reproduction) provides a strong justification for the evolution of a mechanism that regulates lifespan. If such a mechanism did not exist, the chance of an animal in diapause outliving harsh conditions before producing its progeny would be reduced. Because these insulin/IGF-1-like systems can link lifespan with reproduction, a mechanism for regulating lifespan would have selective value, and could arise during evolution.