"We do not see the world as it is, we see the world as we are"
Keywords: ageing, causes of aging, genetics, science of aging, why do people age, why we get old
Over the years, many theories have emerged to explain what process or mechanism drives aging (reviewed in Medvedev, 1990; Weinert and Timiras, 2003). In fact, almost every important discovery in molecular or cellular biology has led to a new family of theories of aging. 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, for example from longevity studies, 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 empirical support than others and this essay aims to present and discuss them. As always in senescence.info, I try to provide a balanced view, even though I of course give more emphasis to the most prominent theories. Like in other fields with little empirical evidence and many conflicting theories, biogerontology is tainted by scientific dogmatism and, even though I have my own favorite theories of aging, I try to follow an open-minded skepticism regarding this crucial yet controversial topic (de Magalhaes, 2005a).
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 crucial (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 the model system 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; Ch'ng et al., 2008). Electron transport chain-mediated longevity also has been shown in C. elegans to involve cell-non-autonomous processes (Durieux et al., 2011). Neurons and the brain might play a regulatory role in aging (Bauer et al., 2005; Bishop and Guarente, 2007), at least to some degree, and organ-specific mediation of lifespan is an emerging area (Rera et al., 2013). For example, one study in mice found that the brain (and the hypothalamus in particular) can modulate longevity due inflammatory signals controlling hormone levels that in turn impact on aging (Zhang et al., 2013). Other results from mice also suggest the existence of systemic factors in aging, but only to some degree (Conboy et al., 2005; Loffredo et al., 2013). Although long-term effects (e.g., on longevity) are unknown, mouse studies on reversing systemic factors have found short-term health and functional benefits (Katsimpardi et al., 2014; Sinha et al., 2014; Villeda et al., 2014). 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 and cell communication is an emerging area of research (Lopez-Otin et al., 2013).
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 what 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 elsewhere, 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) and/or damage from chemical reactions (e.g., Baynes, 2000), while programmed theories argue that aging is predetermined and occurs on a fixed schedule triggered by genetic programs. 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 amount 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 here 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. Perturbations typically refer to genetic manipulations and more details concerning many of the genes discussed are available at the GenAge database. Epistemology in the field of aging is crucial and I think genetic manipulations offer ample, usually unambiguous, evidence with which to understand theories of aging.
Unfortunately, the inevitable conclusion of this section is that the jury is still out regarding mechanisms of aging. Although the search for a pacemaker of age-related changes continues, the bottom line is that all proposed mechanisms can be upregulated by some other--unknown or not--mechanism. The large number of aging theories is proof that our understanding of aging is still far from perfect; to quote David Rollo: "In any field of science, the true degree of understanding is inversely proportional to the number of explanatory theories that prevail." 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. Some theories have gathered more evidence than others and hence may be more promising foci for future research and for developing anti-aging interventions. So please read on the different theories of aging and hopefully you can conjure better theories or determine ways to better test the current theories experimentally.
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