Another View of What Underlies the Reliability Theory of Aging

Around the same time that the reliability theory of aging and longevity was proposed - an extension of existing tools used to determine failure rates in complex financial, electrical and mechanical systems - another paper on the interconnectivity of genes and biochemical processes, insofar as they apply to aging, was published. This was drawn to my attention by the folk at the Immortality Institute forums; I think it provides useful insight-by-comparison into the processes and connections that underly the mathematical models of reliability theory in biological organisms. Being an older paper, the full text is readily available:

The topology of genetic and metabolic networks is organized according to a scale-free distribution, in which hubs with large numbers of links are present. We have developed a computational model of aging genes as the hubs of biological networks. The computational model shows that, after generalized damage, the function of a network with scale-free topology can be significantly restored by a limited intervention on the hubs. Analyses of data on aging genes and biological networks support the applicability of the model to biological aging. The model also might explain several of the properties of aging genes, including the high degree of conservation across different species. The model suggests that aging genes tend to have a higher number of connections and therefore supports a strategy, based on connectivity, for prioritizing what might otherwise be a random search for aging genes.


The decline in physiological function observed during aging differs from that associated with disease: Taffet lists 147 major physiological parameters that decline with age in 22 body systems. Furthermore, the decline is progressive and gradual, initially affecting only physiological reserves. There is no disease that has such a widespread effect on the biological function of an organism. In diseases, some organs and functions are usually affected to a major extent and others only secondarily and in a minor way. Aging-related dysfunction has therefore special properties: it is global (because of the large number of physiological functions declining), generalized (no specific function predominates) and gradual (distributed over a considerable portion of life span). No disease possesses these properties to the same extent. We suggest that aging is the biological dysfunction where network level properties of the genes have the greatest importance. In contrast, disease-related dysfunctions are likely to preferentially involve specific portions of a biological network.


We have tried to address the following questions: Should a view of aging as a generalized process of degradation lead us to be skeptical of recent reports claiming substantial benefits after interventions aimed at single genes? Conversely, do these reports imply that aging is caused by specific genetic programs? How can we reconcile the observed conservation of aging genes among evolutionary very distant species with the prevailing non-adaptive view of aging? Can we propose a model that explains these facts and also makes testable predictions? Can we find initial evidence supporting these predictions? And, finally, can we use this model to devise a more efficient strategy for the search of aging genes?

Network analysis and reliability theory are ways of thinking about the complexities of the aging human body; tools to allow us to interact with levels of complexity that would otherwise be beyond us. Models and tools of this sort don't lead us directly to the hows and whys of aging in terms of precise biochemical mechanisms and explanations. Rather, they steer our thinking towards more effective research, consideration and debate. How important is random genetic and cellular damage to aging? Is it really random? How much more important is any one specific mode of damage over all the rest? How do we best go about enhancing our understanding of the details and importance of line items within known categories of age-related damage?

One important bottom line question relates to whether there are a small number of therapies that will have a comparatively large effect on degenerative aging at a comparatively small cost. The Strategies for Engineered Negligible Senescence (SENS) form a higher level look at this sort of efficiency concern: repair causative damage and put in place preventative measures rather than patch up the resulting problems after the fact. Within the categories of SENS science, however, lie many unanswered questions relating to efficiency: reliability theory, network analysis and similar tools are guides to the future of research and development in this field. We don't have the luxury of time - we need every efficiency we can obtain if we are to see the steps towards radical life extension take place within our lifetimes.

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The reliability theory is very attractive. If you think about genes, gene expression and the pathways they function as a highly redundant and self healing topological network that at first is very efficient but over time is increasingly damaged, you have to wonder whether fixing the accumulated structural damage and pathologies (plaques, cancers, alzheimers, etc) alone will have much of a benefit on aging other than a short term reprieve by allowing the system to function more smoothly. (This is from an overall aging perspect. Don't get me wrong, we clearly want to address these and will still need to.)

From this perspective it would seem that targetted "silver bullet" therapies would indeed help the system to operate more efficiently but only in incremental steps and only for a brief period of time. Damage elsewhere is still occuring due to the fact that entire network as a whole is still weakened from the accumulation of many micro issues dispersed throughout. Perhaps the major ailments, the cancers, alzheimers and most other ailments don't have "root causes" other than the entire network is degraded. Surely a particular DNA mutation or protein misfold can be flagged as the culprit but would they have happened had the network been at full strength? Perhaps the strain on the network as a whole, while it self ajusts to cover for weakened components also exposes weaknesses elsewhere?

Restoring an aged and degraded network though would require not just repair but an ongoing and systematic approach of identifying all of the adjusted pathways and tweaking them at a rate faster than the overall degredation can occur.

The implications of this are significant as it would suggest that it is unlikely that there is one or even a handful of silver bullets that would have a significant impact on aging but rather would require a systems approach of both the constant repair of damage and the management of the genetic network as a whole.

There may not be any shortcuts and we may have to go the full reduction route of mapping every gene to every function and pathway and then devise mechanisms for tweaking all of the gene expressions before we can make significant progress on the aging fight. Let's hope not. We can keep looking for ways to patching up the network the best we can but it might be prudent to consider that we really do need to see both the forest and trees in order to get through it.

Posted by: Maestro949 at June 14th, 2006 4:44 AM
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