Is Aging Genetic? Programmed Aging Versus Wear and Tear

Tooth erosion is a frequent hallmark of aging among different organisms, particularly in mammals (Finch, 1990, pp. 196-202). At a first glance, it would appear that tooth erosion, like many others age-related changes like skin aging, bone aging, etc., is a mere result of wear and tear, similar to materials and objects. However, to quote George Williams (Williams, 1957): "The senescence of human teeth consists not of their wearing out but of their lack of replacement when worn out." The same argument can be made of menopause and female reproductive senescence in general. In mammals, females reach reproductive senescence ultimately because of their lack of oogenesis, and a clear impact of genetics on age of menopause has been demonstrated (de Bruin et al., 2001). Hence aging is not merely a consequence of wear and tear, but rather a consequence of a lack of replacement of the parts. All molecules and cells that compose our body can individually age, but it is the inefficient or lack of replacement of these building blocks that leads to aging.

As detailed before, the teeth of sharks also suffer from wear and tear, but they evolved a mechanism to cope with this problem: they can replace their teeth throughout life. The same holds true for many other species. In some mammals, like rabbits and many rodents, the teeth grow continuously, as an attempt to mitigate the increased wear and tear from their food habits that involve chewing, but this is not a good long-term solution. Long-lived mammals like elephants instead have more than the two sets of teeth. So while wear and tear do contribute to the erosion of teeth, the ultimate cause of tooth erosion is in the genetic program of animals that determines their body plan and its inherited limitations. From this perspective, aging is ultimately genetic. In fact, through genetic and tissue engineering it may soon be possible to create new teeth in the gums of patients (Chai and Slavkin, 2003).

Some have argued that aging has multiple origins and is a mere combination of age-related changes and diseases each timed by independent clocks (Olson, 1987). For instance, some experts have defended that aging derives from the failure of multiple maintenance mechanisms and that there is no basic aging process at all (Holliday, 1995; Peto and Doll, 1997). On the other hand, some defend that aging is genetically programmed. Clearly, some species age due to a precise, uniform genetic clock (Prinzinger, 2005). Semelparous species such as the salmon are such an example, as described before. In these organisms, aging and death follow a very specific, well-timed program analogous to development (Austad, 2004). But humans show a gradual aging process, not sudden death, so the mechanisms of aging in these organisms may not be similar to what happens in humans.

Although the MRDT is only an approximation to rate of aging, it varies widely among similar species (Table 1). Even the pace and/or onset of age-related changes can be remarkably different between similar species, as described elsewhere. On the other hand, the MRDT is remarkably constant among human populations, even under different environmental conditions (Finch, 1990). This robustness of the aging process suggests a strong genetic component. Independently of the environmental conditions of both, a mouse will age 25-30 times faster than a human being. So the reasons why different species age at different paces must be located in the genome. Even though nutrition and exercise can make you live longer and attenuate certain age-related diseases, as discussed elsewhere, you will not be able to live as along as a Galapagos tortoise because humans are genetically programmed to age within a given blueprint. That is not to say that aging evolved with a purpose, a topic debated elsewhere, just like cancer has a strong genetic basis but it did not evolve with a purpose. What it means is that there are precise genetic factors contributing to the pace of aging among different species. In other words, aging is programmed in our genes. There is a molecular clock regulating the aging process. This is further supported by the synchronization of life events among mammals (Finch, 1990, pp. 150-202 & 619). In fact, the aging process of mammals often appears as the same process only timed at different rates.

Species (last common ancestral)	MRDT in years	Observations

Humans	7.6-8.9
Chimpanzees (5.4 Mya)	Similar to humans	Our closest relatives, whose onset of aging occurs considerably earlier than in humans
Old world monkeys (23 Mya)	3.5-4.8 (baboons), 15 (rhesus macaques)	Some primates appear to age about twice as fast as humans
Other non-primates like marmosets, tarsiers, and dwarf and mouse lemurs (60 Mya)		Age considerably fast for primates, showing signs of aging in their second decade of life
Mice and rats (91 Mya)	0.3	Two of the fastest aging mammals
Some common mammals from farm to domestic animals (92 Mya)	3 (dog), 4 (horse), 1.5 (sheep)
Long-lived mammals such as elephants and whales (92 Mya)	8 (elephants)
Slowly aging reptiles (200 Mya)	Often no MRDT detected	Some reptiles appear not to age

The greatest evidence in favor of seeing aging as having a unifying core is the way single genes can modulate the aging process. The plasticity of lifespans in invertebrates shows how a few genes can regulate the entire aging process (Lin et al., 1998; Vanfleteren and Braeckman, 1999; Benard and Hekimi, 2002; Johnson, 2002). In mice, there are several examples of single genes that can extend longevity, in some cases more than 50%, increase the MRDT, and delay the onset of multiple age-related changes and diseases (Liang et al., 2003; de Magalhaes et al., 2005a). These results clearly argue that genetic mechanisms can, up to a certain degree, regulate aging in mammals. (These genes and their mechanisms are further detailed ahead.) Moreover, it has been argued that the rapid evolution of longevity in the human lineage indicates that maybe a small number of genes are able to regulate the pace of aging (Cutler, 1975).

One of the most intriguing phenotypes in the biology of aging is the accelerated aging witnessed in humans and animals as a result of certain mutations. Progeroid syndromes, as they are called, are rare genetic diseases that originate a phenotype that is similar to accelerated aging. The three most studied such syndromes are Werner's (WS), Cockayne, and Hutchinson-Gilford's syndrome (Martin, 1978; Martin and Oshima, 2000). Though patients with Down syndrome or trisomy 21 often also exhibit progeroid features (Martin, 1978; Raji and Rao, 1998), this disease has not gathered as much attention from the perspective of aging research as the other three syndromes named above.

In particular patients with WS exhibit striking features resembling accelerated aging and show an early onset--compared to normal aging--of multiple age-related diseases like diabetes, cataracts, osteoporosis, baldness, and atherosclerosis (Goto, 1997; Fig. 1). Though differences exist in terms of pathology, what most markedly distinguishes these syndromes is age of onset with Hutchinson-Gilford's and Cockayne syndrome almost exclusively affecting children while WS patients normally reach adulthood. There are also five reported cases of a neonatal form of progeria called Wiedemann-Rautenstrauch syndrome, in which babies appear to be born old, but further research is needed to confirm or dismiss such cases as accelerated aging (Rodriguez et al., 1999; Arboleda et al., 2007).

George Martin suggested that WS mimics about 50% of aging characteristics: early cataracts, old skin, gray hair, etc., but not brain aging (Martin, 1982; Gosden, 1996, p. 126). This is a high proportion since it is not clear that these diseases are indeed accelerated aging. Moreover, the WS phenotype tends to affect tissues where WRN, the gene in which mutations result in WS (Yu et al., 1997), is expressed (Motonaga et al., 2002), so it makes sense that not all organs display signs of accelerated aging in WS. Such diseases demonstrate the hierarchical essence of aging in which a single gene can regulate a vast array of complex age-related changes. (Further details concerning these diseases are presented in another essay.)

One key discovery in the biology of aging was made in 1935, following earlier findings (Osborne et al., 1917), by veterinary nutritionist Clive McCay and colleagues. As previously mentioned, they discovered they could slow aging in laboratory rats just by making them eat less calories while maintaining normal levels of proteins, vitamins, and minerals (McCay et al., 1935). This process became known as caloric restriction (CR) and appears to work in many animals; it has been particularly well-studied in mice. From mice, we know that CR not only increases longevity by up to 50% but it also postpones or diminishes the incidence of most age-related diseases, decreases the rate of aging, and delays development (reviewed in Weindruch and Walford, 1988; de Magalhaes et al., 2005a). Doubts have for long existed on whether CR results from some technical artifact. Even so, CR remains the most impressive way to delay aging in mammals, particularly since it derives from a very simple intervention. Like WS, CR demonstrates how it is possible to delay the aging process as a whole, suggesting that aging has a unifying clock. (The mechanisms of CR are still under debate but are further discussed in another essay.)

Like many others (Miller, 1999), I think there is a fundamental process of aging that gives rise to aging. There is a uniform, unifying genetic core that synchronizes most facets of aging. Nonetheless, it is plausible that some age-related diseases are independent of this core process. For example, Machado-Joseph is a neurodegenerative genetic disease with a typical adult onset that results from a single gene defect that appears to result in a toxic form of the protein (Sequeiros et al., 1994). Similarly, many genes can influence individual age-related changes (Martin, 1982). Furthermore, there is a great variability in age-related changes among individuals, suggesting that lifestyle can influence aging to some degree (Finch, 1990, pp. 317-352). In conclusion, while there is a basic process of aging and there may even be a single mechanistic clock, age-related changes in individual organs may be subject to unique constraints, both environmental and genetic.

Although the aim of my work is the overall aging phenotype, I believe that focusing on these fundamental causes of aging, the genetic basis for differences in rate of aging between similar species and between individuals, is the most appropriate strategy (de Magalhaes, 2003), an idea defended by many others (Comfort, 1968). The true proportion of diseases that are independent of the fundamental cause of aging seem low, but I cannot exclude that the impact of such fundamental mechanisms is overestimated. Still, humans do not appear to have death genes like the salmon, and the essence of those unifying genes and mechanisms are discussed elsewhere.

As mentioned before, more resources are aimed at curing age-related diseases than aging, or senescence, itself. This is partly due to the belief that aging is a complex, difficult to understand process that has eluded generations of gerontologists. Such way of thinking has led to complacency, and unambitious objectives. On the other hand, if one thinks aging is caused by a unifying mechanism, objectives become more ambitious. Of course that just because aging has a genetic core does not mean that curing it will be easy. Naturally occuring genetic variants in mice can delay aging, but only to a certain point. Therefore, even when we identify the genetic mechanisms behind human aging, curing aging will be an Herculean task.

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Is Aging Genetic?

Wear and Tear

Multiple versus Unifying Mechanisms of Aging