Systems biology of ageing and longevity

Abstract

Ageing is intrinsically complex, being driven by multiple causal mechanisms. Each mechanism tends to be partially supported by data indicating that it has a role in the overall cellular and molecular pathways underlying the ageing process. However, the magnitude of this role is usually modest. The systems biology approach combines (i) data-driven modelling, often using the large volumes of data generated by functional genomics technologies, and (ii) hypothesis-driven experimental studies to investigate causal pathways and identify their parameter values in an unusually quantitative manner, which enables the contributions of individual mechanisms and their interactions to be better understood, and allows for the design of experiments explicitly to test the complex predictions arising from such models. A clear example of the success of the systems biology approach in unravelling the complexity of ageing can be seen in recent studies on cell replicative senescence, revealing interactions between mitochondrial dysfunction, telomere erosion and DNA damage. An important challenge also exists in connecting the network of (random) damage-driven proximate mechanisms of ageing with the higher level (genetically specified) signalling pathways that influence longevity. This connection is informed by actions of natural selection on the determinants of ageing and longevity.

Figure 1.

The genetic regulation of ageing and longevity as explained by the disposable soma theory. Survival in the wild is curtailed by extrinsic mortality and all that is required of the body's maintenance and repair functions is that they should preserve vitality until an age when the chance of remaining alive is small. Genetic control of longevity is effected by setting the many different maintenance and repair functions to provide a sufficient but not excessive period of longevity assured. In some species, there appears to have evolved a capacity to respond to varying resource levels by high-level, nutrient-sensing pathways that co-ordinately alter the investments in maintenance and repair. This can serve to fine-tune optimal resource allocations in order to accommodate environmental fluctuations, such as periods of famine.

Figure 2.

Feedback loop responsible for initiating and maintaining growth arrest in senescent cells (adapted from Passos et al. [23]). Damage may arise in mitochondria, by telomere erosion, or by induction of lesions in non-telomeric chromosomal DNA. Once initiated, feedback proceeds (see text), eventually locking the cell in a state of permanent arrest.

Figure 3.

Alternative cellular responses to damage. Depending on cell type, the normal response to detection of damage will be either to delete the cell by apoptosis or to arrest cell division permanently by senescence. Both of these outcomes will result in impaired tissue homeostasis, contributing to ageing of the organism. Failure to eliminate or arrest damaged cells will leave them vulnerable to accumulating further damage, which may result in cancer.