Why Do We Age?

"We do not see the world as it is, we see the world as we are"

The Talmud

Keywords: ageing, biogerontology, genetics, science of aging

Over the years, many theories have emerged to explain what changes lead to aging (reviewed in Medvedev, 1990). Most theories of aging have old origins, but the inherent difficulties of studying human aging--such as the lack of adequate models--make testing these theories a difficult, lengthy, and expensive process. Moreover, interpreting the results is frequently controversial; discriminating between causes and effects of aging is often impossible. That is why, at present, no consensus exists over what causes aging, what determines rate of aging across mammals, or what changes occur in humans from age 30 to 70 to increase the chances of dying by over 30-fold. Nevertheless, some theories have gathered more experimental support than others and this essay aims to present them. Yet remember to treat theories of aging like you treat girlfriends: love them, spend time with them, respect them, but always be on the lookout for a new, exciting theory.

Aging is a largely mysterious process. The aging process may derive from changes occurring in parallel in different tissues due to intrinsic cellular mechanisms or changes in one tissue may be predominant. Some authors argue that aging is located within one tissue such as the brain (e.g., Mattson et al., 2002) while others defend that aging originates in all tissues (e.g., Kowald and Kirkwood, 1994). Some researchers even argue that one type of cells such as bone marrow stem cells may be determinant (Geiger and Van Zant, 2002; Van Zant and Liang, 2003). "Big bang" reproduction demonstrates how one particular system, often the endocrine system, can regulate aging (see Gosden, 1996 for arguments). Results from C. elegans indicate that a few lineages in mosaic organisms confer longevity (Apfeld and Kenyon, 1998; Hsin and Kenyon, 1999; Lin et al., 2001; Arantes-Oliveira et al., 2002; Patel et al., 2002), perhaps due to endocrine signals (Wolkow et al., 2000). Some results from mice also suggest the existence of systemic factors in aging, but only to some degree (Conboy et al., 2005). On the other hand, as mentioned previously, it appears that intrinsic changes occur in human cells as we age (de Magalhaes, 2004). Although this debate has not been settled yet, it appears that intrinsic cellular mechanisms play a role in aging, though these can be modulated by extracellular factors like hormones.

There are many types of theories of aging. I could have divided this section in many different ways, but I think it makes sense to divide it into damage-based and programmed theories of aging. Damage-based theories, as the name implies, defend that aging results from a continuous process of damage accumulation originating in by-products of metabolism; in other words, a certain form of damage accumulates throughout the entire lifespan and causes most aspects of I previously defined as aging. Typically, this damage is a by-product of normal cellular processes, or a consequence of inefficient repair systems. On the other hand, programmed theories of aging argue that aging is not a result of random or stochastic process but rather driven by genetically regulated processes.

As argued before, aging has a strong genetic component. Even damage-based theories of aging recognize that certain genetic factors, such as defensive or protective genes, play a role in aging (Kirkwood and Austad, 2000). Likewise, programmed theories of aging recognize that some forms of damage contribute to aging and that environmental factors influence the outcome of aging to some degree. So the difference between these two camps lies in the underlying mechanism: damage-based theories of aging argue that aging is predominantly a result of interactions with the environment (e.g., Holliday, 2004), while programmed theories argue aging is predetermined and occurs on a fixed schedule. Others have suggested similar segregations of theories of aging (e.g., Cutler, 1979). For instance, it has been proposed that aging could be: 1) a result of extrinsic or intrinsic factors that cause an accumulation of damage; or 2) that aging is a result of changes in gene expression that are either programmed or derived from DNA structural changes (Campisi, 2000). As will become apparent, however, a certain amoung of overlap between theories of aging is possible.

One of the major problems in developing a coherent aging theory is separating causes from effects. As any statistician will tell you, "Correlation does not mean causation." Just because two processes parallel each other we cannot imply a causal relation in any direction. Therefore, it is extraordinarily difficult to predict which, if any, mechanistic theory of aging is correct. One way to infer the impact on aging of the pathways described herein is using a system-level approach. By perturbing each component of a pathway under study and integrating the observed effects it is possible to discriminate causes from effects and formulate new hypotheses (de Magalhaes and Toussaint, 2004b). While interpreting theories of aging I try to follow a system-biology approach based on, if any, published perturbations of the pathway's components. More details concerning these genes involved are available at the GenAge database.

The conclusion for this section is that no conclusions can be made--there, I took the suspense away. Although the search for a pacemaker of age-related changes continues, the bottom line is that these can all be upregulated by some other, unknown or not, mechanism. Even so, and since there are more doubts than answers in gerontology, we should not discard these theories easily. Life, and marveling life and death as we do in gerontology, is a game of probabilities. So please read on the different theories of aging and hopefully you can determine better ways to test them experimentally.

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