Programmed Theories of Aging

In addition to damage-based theories, a second class of theories of aging defends that aging is a genetically-determined, programmed process. In this essay, I present and review the most important concepts and theories. As mentioned elsewhere, in most species, aging does not appear to be programmed in the sense that it serves a purpose (Austad, 2004). Though there have been arguments in favor of seeing aging as part of a predetermined plan, in this essay, by "programmed" I mean "genetically regulated" in the sense of following instructions.

Keywords: ageing, biogerontology, deterministic theories of aging, genetics, geriatrics, life span, pre-programmed aging, programmed aging

The Endocrine System as the Pacemaker of Aging

The idea that hormonal changes drive aging is an old one (reviewed in Gosden, 1996). Since the levels of certain hormones decline with age, like growth hormone (Ho et al., 1987) and its downstream target insulin-like growth factor I or IGF-1 (Hammerman, 1987), many old and current anti-aging products are based on the idea of restoring these levels. As briefly introduced before, however, it appears that restoring hormonal levels to youthful levels does not deter aging and may even accelerate the aging process. Still, it is possible that the endocrine system influences aging as will now be briefly reviewed.

CR has been associated with hormonal alterations in rodents, such as decreasing plasma levels of insulin (Masoro et al., 1992) and IGF-1 (Breese et al., 1991), and an increase in growth hormone secretory dynamics (Sonntag et al., 1999). Interestingly, several genes have been identified in model organisms whose effects appear to mimic CR. The best example is probably the urokinase-type plasminogen activator. Overexpression of this gene in the brain of mice causes a decrease in appetite resulting in a 20% decrease in food consumption and body mass, and a 20% increase in longevity (Miskin and Masos, 1997). Other genes appear to result in a phenotype similar to CR in generally affecting body size, growth hormone and IGF-1, and body temperature (reviewed in Bartke et al., 2001a). For instance, mice homozygous for Pit1 have lower growth hormone and IGF-1 levels; they are dwarf, live about 40% longer, their maximum lifespan is increased, and their aging process appears to be delayed (Flurkey et al., 2001). Mice mutant for Prop1, a transcription factor that regulates Pit1, live 50% longer (Brown-Borg et al., 1996). Likewise, mice overexpressing bovine growth hormone appear to age faster (Bartke, 2003). However, by combining CR and mutations of one of these genes--the Prop1 gene--, we witness an even greater increase in longevity, suggesting that distinct mechanisms may be at work (Bartke et al., 2001b). Recent results suggest that although the growth hormone/IGF-1 pathway is involved in CR, other mechanisms might also operate (Shimokawa et al., 2003). Whatever the exact mechanisms, CR appears to operate through a neuroendocrine signaling cascade of which the GH/IGF-1 axis is a pivotal, though probably not the only, component (Masoro, 2005). These results hence link some aspects of energy metabolism to aging via the GH/IGF-1 axis (reviewed in Berner and Stern, 2004).

Many experiments in different model organisms associated the insulin/insulin-like pathways with aging (Lin et al., 2000; Clancy et al., 2001). As mentioned earlier, smaller mice, horses, and dogs appear to live longer and this could be related to lower levels of IGF-1 (Miller, 1999; Miller et al., 2002a). Some studies suggest that insulin-like growth factor I may affect human longevity (Bonafe et al., 2003). Human patients with a mutated Prop1 gene may live slightly longer (Bartke et al., 2001a), though the matter is a bit more complicated because patients with deficiencies in GH and IGF-1 show signs of early aging but their lifespan may actually be increased (Laron, 2005) and untreated patients with growth hormone deficiency have a reduced longevity (Besson et al., 2003). Notheless, it is clear that neuroendocrine systems can impact on aging and possibly on human aging as well (Bartke, 2005; de Magalhaes, 2005a). Please take a look at the list of genes that can modulate the aging phenotype available in GenAge as many are related to the GH/IGF-1 axis.

One putative player in aging is the klotho gene, which acts as a circulating hormone. Mutations in klotho appear to accelerate the aging process (Kuro-o et al., 1997). In contrast, overexpression of klotho extend lifespan by about 30%. Its functions are largely unknown but it could be related to insulin/IGF-1 signaling (Kurosu et al., 2005).

It is unknown, however, what are the exact mechanisms of action of these hormones. Several possibilities exist (reviewed in Berner and Stern, 2004). It has been proposed that the GH/IGF-1 axis regulates antioxidants (Brown-Borg et al., 2005). Another hypothesis is that since growth hormone and IGF-1 are mitogens, lower levels of the GH/IGF-1 axis decreases cellular replication that impacts on some sort cellular clock (Sonntag et al., 1999; Bowen and Atwood, 2004; de Magalhaes and Faragher, 2008). Similarly, maybe the GH/IGF-1 axis impacts on cellular processes like apoptosis or stress resistance (Sapolsky et al., 1986). As mentioned below, maybe hormonal changes regulate aging as indirect consequences of the developmental program. The jury is still out.

Overall, the GH/IGF-1 axis and associated neuroendocrine mechanisms--some of which still unknown--appear to influence mammalian aging. How exactly this happens is not known and the signal transduction involved in the GH/IGF-1 axis remains largely a mystery.

The Developmental Theory of Aging

As mentioned previously, the dauer pathway in C. elegans is an alternative developmental pathway that results in a significant life-extension (Klass and Hirsh, 1976). In the dauer pathway, which can be activated by starvation and hence may be analogous to CR, there is a developmental arrest, which suggests that, at least in this model system, aging and development are coupled (Johnson et al., 1984). Further genes influencing lifespan in C. elegans confirm a linkage between the timing of development and the timing of aging (Lakowski and Hekimi, 1996). In insects too arrested development due to environmental factors has been suggested to slow or even stop aging (Tatar and Yin, 2001). Other examples exist (reviewed in Brakefield et al., 2005): in the marine mollusk Phestilla sibogae, the length of larval life is determined by a chance encounter with a stimulus that causes metamorphosis. Interestingly, the duration of post-larval life is unaffected by the length of the time it takes the larva to metamorphose. In other words, during the developmental hiatus from the onset of larval metamorphic competence to metamorphosis, aging is suspended (Miller and Hadfield, 1990). Similarly, semelparous species like the salmon, described earlier, clearly argue that developmental programs can cause aging, or a phenotype resembling aging, and death (de Magalhaes and Church, 2005). Lastly, as mentioned before, there is a correlation in higher animals, including in mammals (Fig. 1), between the time it takes to reach sexual maturity and how long, on average, they live afterwards (Charnov, 1993). This could be due to similar extrinsic mortality rates acting on animals, however, and may thus be a product of co-evolution rather than a causal relation.

Mammalian lifespan

Figure 1: The life history events of mammals, such as development, reproduction, and aging, typically occur in proportion to the entire lifespan. (Adapted from de Magalhaes and Sandberg, 2005.)

Of course, these are distant animal models and these findings may not be representative of human biology, but they demonstrate how, at least in some species, aging is a result of the genetic program that also controls development. The developmental theory of aging--also called DevAge--defends that aging is a result of development, that aging and development are regulated by the same genetic mechanisms and processes (Medvedev, 1990; Kanungo, 1994; Zwaan, 2003; Bowen and Atwood, 2004; de Magalhaes and Church, 2005). Another way of looking at aging from this perspective is considering the idea that damage only begins accumulating after developmental processes are completes and it is this developmentally-triggered damage that causes most aspects of aging.

Although it can be argued that, in some species, aging is a direct product of evolution, as debated before, such possibility appears unlikely in higher animals, such as mammals that rear their offspring. Instead, one argument is that aging is an unintended product of evolution, an unintended product of selection acting on development. Evolution does not favor long life. Rather, evolution optimizes developmental mechanisms for reproduction. Once an organism has passed its genes to the next generation maybe evolution gives up on it and the same genes responsible for the growth and maturation of that organism will inadvertently end up killing it (de Magalhaes and Church, 2005). Evolutionary, this can be seen as a form of antagonistic pleiotropy (Williams, 1957), one in which alleles beneficial early in life are harmful late in life.

The insulin-like pathway appears to play a role in animals choosing the dauer pathway (e.g., Wolkow et al., 2000; Lin et al., 2001). As mentioned above, endocrine regulation appear to have an effect on aging, while indirectly affect growth and maturation. The way neuroendocrine systems limit longevity suggests a link between reproduction and lifespan (Mobbs, 2004). Thus, maybe some hormones like growth hormone and genes involved in insulin-like signaling regulate growth and development early in life and later contribute to aging (de Magalhaes and Church, 2005). Early studies showed that CR stunted growth and sexual development (McCay et al., 1935), though the extent of which depends on the severity of the CR used. Interestingly, high nutrition may accelerate maturation and decrease lifespan in ground squirrels (Harvey and Zammuto, 1985). Therefore, maybe seeing aging as a consequence of development links the impact of the endocrine system on aging to CR.

The way mammalian aging is similar in different species, sometimes appearing as the same process only timed at different paces, has puzzled researchers (Finch, 1990; Miller, 1999). If the timing of development is linked at a mechanistic and genetic level to rate of aging in mammals that would explain the plasticity of the aging process in mammals and how a process escaping natural selection is so similar among them. Assuming a link between the genetic mechanisms regulating development and aging would also explain how aging has changed so rapidly in primates (Cutler, 1979; Allman et al., 1993). Hence, one hypothesis is that, probably driven by an extended brain development (Cutler, 1979; Allman et al., 1993; Kaplan and Robson, 2002; Lee, 2003), hominid evolution led to an extension of development which in turn led to a delay of aging.

While the developmental theory of aging is theoretically sound, it lacks many concrete details for how developmental mechanisms could influence age-related changes. Some theoretical models exist, such as for brain aging (de Magalhaes and Sandberg, 2005), but there are still many details that are unknown. Also, there is no reason to doubt that, at least, some age-related changes are the result of an accumulation of some toxic by-product of metabolism, so an overlap between theories of aging may exist. Still, the developmental theory of aging argues that the bulk of the aging phenotype is due to the indirect actions of developmental mechanisms.

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